Development of Store-Operated Calcium Entry-Targeted Compounds in Cancer

Abstract

Store-operated Ca²⁺ entry (SOCE) is the major pathway of Ca²⁺ entry in mammalian cells, and regulates a variety of cellular functions including proliferation, motility, apoptosis, and death. Accumulating evidence has indicated that augmented SOCE is related to the generation and development of cancer, including tumor formation, proliferation, angiogenesis, metastasis, and antitumor immunity. Therefore, the development of compounds targeting SOCE has been proposed as a potential and effective strategy for use in cancer therapy. In this review, we summarize the current research on SOCE inhibitors and blockers, discuss their effects and possible mechanisms of action in cancer therapy, and induce a new perspective on the treatment of cancer.

Introduction

The Overview of Store-Operated Calcium Entry

Store-operated calcium entry (SOCE) is typically activated by ligands of cell surface receptors such as G proteins that activate phospholipase C (PLC) to cleave phosphatidylinositol 4, 5-bisphosphate (PIP2) and produce inositol 1, 4, 5-trisphosphate (IP3). IP3 binds to IP3 receptors (IP3R) on the endoplasmic reticulum (ER) membrane, leading to the release of Ca²⁺ from the ER. Cells respond to this depletion of ER intraluminal Ca²⁺ by opening Ca²⁺ channels to allow cellular influx, which is also the provenance of “SOCE.” Researchers have been exploring the mechanisms and functions of SOCE since its discovery and definition, and it has been found that stromal interaction molecules (STIMs) and ORAI family proteins are the two major participants in SOCE (Hogan et al., 2010; Prakriya and Lewis, 2015).

STIM proteins (STIM1 and STIM2) are located on the ER membrane and are essential for SOCE (Williams et al., 2001; Liou et al., 2005; Roos et al., 2005). STIM1 contains an ER-luminal portion (containing two EF-hands and a sterile α-motif (SAM) domain), a single transmembrane segment, and a cytoplasmic portion (containing a coiled-coil domain (CCD), a STIM-ORAI-activating region (SOAR) or CRAC activation domain (CAD), a serine- or proline-rich segments and a polybasic (PB) C-tail) (Hogan et al., 2010; Xie et al., 2016). STIM2 has a structure similar to STIM1 but a critical residue difference in the SOAR domain, which endows STIM2 with partial agonist properties and competitive inhibiting functions in STIM1-mediated Ca²⁺ entry, thereby maintaining basal cytoplasmic Ca²⁺ levels by preventing uncontrolled activation of ORAI proteins (Brandman et al., 2007; Wang et al., 2014).

ORAI proteins are plasma membrane (PM) channels that can be gated by STIMs for Ca²⁺ entry during SOCE. Three homologs of ORAI have been identified in humans, namely, ORAI1, ORAI2, and ORAI3 (also called CRACM1-3), among which, ORAI1 is the most potent and has been extensively studied. ORAI1 contains four transmembrane helices (TM1-TM4), an intracellular location domain (including N-terminal and C-terminal epitope tags) and an extracellular location domain (including an epitope tag introduced into the TM3-TM4 loop). The N-terminus and C-terminus of ORAI1 intracellular sites are essential for the interaction with STIM1 and the opening of the ORAI1 channel (Peinelt et al., 2006; Vig et al., 2006; Hogan et al., 2010; Xie et al., 2016). The homologs, ORAI2 and ORAI3 primarily differ in cytosolic N-terminal, C-terminal and 3–4 loop sequences (Amcheslavsky et al., 2015), and they mediate SOCE in a manner similar to that of ORAI1, but they differ in permeability properties and inactivation (Lis et al., 2007), leading to augmented SOCE efficacy in the order ORAI1 > ORAI2 > ORAI3 (Mercer et al., 2006).

When STIM1 residing in the ER lumen senses a Ca²⁺ decrease in the ER, it initiates conformational changes and oligomerization, overcoming the intracellular autoinhibition mediated by CC1 to expose SOAR/CAD and the PB C-tail. Activated STIM1 multimerizes and migrates toward the PM, where it interacts with the intracellular regions of ORAI1, resulting in ORAI1 activation and Ca²⁺ influx (Figure 1) (Liou et al., 2005; Park et al., 2009; Yuan et al., 2009; Zhou et al., 2010).

FIGURE 1

Transient receptor potential proteins (TRPs) contain similar structures, consisting of six transmembrane-helical domains (TM1-TM6) with a loop between TM5 and TM6 and cytoplasmic N- and C-termini (Venkatachalam and Montell, 2007). TRP channels, especially TRPC channels, have been proposed as candidate components of SOCE, although this assignment is still disputed, under certain conditions, several TRPC channels can function in SOCE pathways (Prakriya and Lewis, 2015). For example, in HEK-293 cells, the knockdown of TRPC1, TRPC3 or TRPC7 dramatically reduced the SOCE activated by passive Ca²⁺ store depletion, while inhibition of TRPC4 or TRPC6 had no effect on SOCs activity (Zagranichnaya et al., 2005). However, in human corneal epithelial cells, mouse endothelial cells and mouse mesangial cells, TRPC4 deficiency decreased SOCE (Tiruppathi et al., 2002; Wang et al., 2004; Yang et al., 2005). Furthermore, TRPC3 and TRPC7 effects on SOCE depend on their expression levels. At low expression levels, they are activated by passive Ca²⁺ store depletion and act as SOCE, while at high expression levels, they behave as Ca²⁺ store-independent Ca²⁺ influx channels (Worley et al., 2007). Therefore, it is necessary to continue to explore the function of TRPCs in SOCE.

Role of Store-Operated Calcium Entry in Cancer

Accumulating evidence has revealed that many cancers, such as breast, liver, lung, gastric, colon, and ovarian cancer, exhibit augmented SOCE and overexpression of STIM1 or ORAI1. SOCE inhibition through STIM1 or ORAI1 knockdown inhibits the proliferation and metastasis of cancer cells, suggesting that SOCE may act as an oncogenic pathway (Yang et al., 2009; Chen et al., 2011; Yoshida et al., 2012; Motiani et al., 2013; Yang et al., 2013; Zhang et al., 2013; Kim et al., 2014; Umemura et al., 2014; Wang et al., 2015; Xu et al., 2015; Schmid et al., 2016; Xia et al., 2016; Goswamee et al., 2018; Wang Y. et al., 2018; Zang et al., 2019; Huang et al., 2020). In addition, SOCE is believed to promote tumor angiogenesis through the increased secretion of VEGF by endothelial and cancer cells. For example, in cervical cancer, STIM1 regulates the production of VEGF to control the formation of blood vessels, and the formation of tumor could be impaired by inhibiting STIM1 (Chen et al., 2011). In addition, the potential therapeutic value of targeting SOCE in cancer has further been supported by the fact that STIM- and ORAI- mediated SOCE is essential for the secretion of cytokines and chemokines from T cells, mast cells, and macrophages, as well as in the differentiation and functions of CD4⁺ and CD8⁺ T cells. For example, the inhibition of SOCE by genetic deletion of ORAI1, STIM1, or STIM2 in murine CD4⁺ T cells impaired Th17 cell function, causing a decrease in the production of IL-17, which is believed to be proinflammatory factor important for tumor progression (Ma et al., 2010; Shaw et al., 2014; Mehrotra et al., 2019). Moreover, as candidate components of SOCE, TRP channels have been found to affect the survival, proliferation, and invasion of cancer cells (Shapovalov et al., 2016). For example, TRPC1 was confirmed to play different roles in tumorigenesis, inhibition of TRPC1 by siRNA or SOCE inhibitors could suppress the proliferation and invasion of cancer cells including nasopharyngeal carcinoma, malignant glioma and non-small-cell lung carcinoma (Bomben and Sontheimer, 2010; He et al., 2012; Tajeddine and Gailly, 2012).

In summary, SOCE promotes the proliferation and metastasis of cancer cells, and enhances tumor angiogenesis and the formation of a tumor-promoting inflammatory environment. Inhibition of SOCE may be a potential and effective therapy for cancers. In this review, we summarize the available inhibitors of SOCE (Tables 1, 2), discuss their effects and possible mechanisms (Table 3), and introduce a new viewpoint on the treatment of cancer.

TABLE 1

Compound	Structure	IC50 of SOCE inhibition	References
SKF96365		IC50 = 10.2 ± 1.2 μM in VSMCs	Zhang et al. (1999)
		IC50 = 12 μM in Jurkat T cells	Chung et al. (1994)
		IC50 = 1.2 μM in arterioles	McGahon et al. (2012)
		IC50 = 60 μM in PLP-B lymphocyte cells	Dago et al. (2018)
2-APB		IC50 = 4.8 ± 0.6 μM in DT40 cells	Goto et al. (2010)
		IC50 = 3.7 μM as inhibitor, >100 μM as activator in arterioles	McGahon et al. (2012)
		IC50 = 3 μM in CHO cells	Ozaki et al. (2013)
		IC50 = 17 ± 1 μM in human platelets	Giambelluca and Gende (2007)
		IC50 = 15 μM in Jurkat T cells	Suzuki et al. (2010)
DPB-162AE		IC50 = 27 ± 2 nM in DT40 cells	Goto et al. (2010)
		IC50 = 190 ± 6 nM in CHO cells	Goto et al. (2010)
		IC50 = 200 nM in HEK293 cells	Hendron et al. (2014)
		IC50 = 0.32 μM in Jurkat T cells	Suzuki et al. (2010)
DPB-163AE		IC50 = 42 ± 3 nM in DT40 cells	Goto et al. (2010)
		IC50 = 210 ± 20 nM in CHO cells	Goto et al. (2010)
		IC50 = 600 nM in HEK293 cells	Hendron et al. (2014)
		IC50 = 0.43 μM in Jurkat T cells	Suzuki et al. (2010)
BTP2		IC50 = 100 nM in Jurkat T cells	Ishikawa et al. (2003)
		IC50 = ∼10 nM in peripheral blood T-lymphocytes	Zitt et al. (2004)
		IC50 = 0.1–0.3 μM in HEK293 cells, DT40 B cells and A7r5 smooth muscle cells	He et al. (2005)
		IC50 = 0.59 μM in RBL-2H3 cells	Schleifer et al. (2012)
Pyr3		IC50 = 0.5 μM in E13 cortical neurons	Gibon et al. (2010)
		IC50 = 0.54 μM in RBL-2H3 cells	Schleifer et al. (2012)
Pyr6		IC50 = 0.49 μM in RBL-2H3 cells	Schleifer et al. (2012)
Pyr10		IC50 = 13.08 μM in RBL-2H3 cells	Schleifer et al. (2012)
GSK-5498A		IC50 = ∼1 μM in human embryonic kidney cells	Rice et al. (2013)
		IC50 = 3.7 μM in ASMCs	Chen and Sanderson (2017)
GSK-5503A		IC50 = ∼4 μM in HEK cells	Derler et al. (2013)
GSK-7975A		IC50 = ∼4 μM in HEK cells	Derler et al. (2013)
		IC50 = 4.1 μM in ASMCs	Chen and Sanderson (2017)
		IC50 = 0.34 μM in HLMCs	Ashmole et al. (2012)
Synta66		IC50 = ∼1 μM in Jurkat T cells	Di Sabatino et al. (2009)
		IC50 = 3 μM in RBL-1 mast cells	Ng et al. (2008)
		IC50 = 0.25 μM in HLMCs	Ashmole et al. (2012)
CAI		IC50 = 2∼5 μM in Huh-7 cells	Enfissi et al. (2004)
CM4620		IC50 = 120 nM for ORAI1/STIM1-mediated SOCE in HEK 293 cells	Wen et al. (2015); Waldron et al. (2019)
		IC50 = 900 nM for ORAI2/STIM1-mediated SOCE in HEK 293 cells
ML-9		IC50 = ∼16 μM in HEK293 cells	Smyth et al. (2008)
NPPB		IC50 = 5 μM in Jurkat T cells	Li et al. (2000)
AnCoA4		Not found	Not found
RO2959		IC50 = 402 ± 129 nM in RBL-2H3 cells	Chen G. et al. (2013)
		IC50 = 265 ± 16 nM in CD4+ T cells	Chen G. et al. (2013)
YZ129		IC50 = 820 ± 130 nM in HeLa cells	Liu et al. (2019)
MRS-1845		IC50 = 1.7 μM in HL-60 cells	Harper et al. (2003)
DES		IC50 = ∼1 μM in GBM cells	Liu et al. (2011)
Mibefradil		IC50 = 52.6, 14.1, and 3.8 μM for ORAI1, ORAI2, and ORAI3 respectively in HEK-293 T-REx cells	Li et al. (2019)

Structures and IC₅₀ of compounds.

Store-Operated Calcium Entry-Targeted Compounds in the Application of Cancer Treatment

SKF 96365

(1-[2-(4-Methoxyphenyl)-2-[3-(4-Methoxyphenyl)propoxy]ethyl]imidazole;hydrochloride)

SKF 96365 is structurally distinct from classic Ca²⁺ antagonists, drugs or compounds that inhibit Ca²⁺ entry by directly inhibiting Ca²⁺ channels or affecting Ca²⁺ pools. It shows selectivity in blocking receptor-mediated Ca²⁺ entry (RMCE), the Ca²⁺ influx that is independent of depolarization and caused by receptor occupation, leading to a significant increase in [Ca²⁺]i biologically, with no impact on internal Ca²⁺ release in platelets, neutrophils or endothelial cells (Spedding, 1982; Merritt et al., 1990; Cabello and Schilling, 1993), and the inhibition of RMCE exerted by SKF 96365 could inhibit [3H]-thymidine incorporation, interleukin-2 (IL-2) synthesis and cell proliferation of peripheral blood lymphocytes (Chung et al., 1994). It was also found that SKF 96365 could block store-independent TRP channels in osteoclasts and capacitative Ca²⁺ entry (CCE) in astrocytes (Wu et al., 1999; Bennett et al., 2001).

Iwamuro et al. found, for the first time, that SKF 96365 sensitively inhibited the SOCE activated by ET-1 at high concentrations (Iwamuro et al., 1999). As a SOCE inhibitor, SKF 96365 was reported to inhibit cell proliferation in many cancers by inducing cell apoptosis and cell cycle arrest in G2/M phase (Nordström et al., 1992; Lee et al., 1993; Arias-Montaño et al., 1998; Cai et al., 2009; Zeng et al., 2013; Zhang et al., 2015; Jing et al., 2016; Wang W. et al., 2018). Autophagy seems to play different roles in the pharmacological mechanism of SKF 96365. Inhibition of SOCE by SKF 96365 inhibited the AKT/mTOR pathway, induced autophagic cell death and decreased the survival, and proliferation of PC3 and DU145 prostate cancer cells (Selvaraj et al., 2016), while in colorectal cancer cells, SKF 96365 was reported to induce cytoprotective autophagy to delay apoptosis through the inhibition of calcium/calmodulin-dependent protein kinase IIγ (CaMKIIγ)/AKT signaling cascade, and autophagy inhibition could significantly augment the anticancer effect of SFK 96365 in mouse xenograft models (Jing et al., 2016).

In addition, SKF 96365 could also effectively inhibit the metastasis of cancers. It could impair the assembly and disassembly of focal adhesions of breast cancer cells (Yang et al., 2009), block the formation and activity of invadopodium in melanoma cells (Sun et al., 2014), and it could also inhibit cell migration by inactivating non-muscle myosin II and reducing actomyosin formation and contractile force in cervical and non-small cell lung cancer (NSCLC) cells (Chen Y.-T. et al., 2013; Wang Y. et al., 2018). In addition to inhibiting growth and colony formation independently through the blockage of Ca²⁺ channels, for example, through the blockage of TRPC channels in glioma cells (Bomben and Sontheimer, 2008; Ding et al., 2010; Song et al., 2014), SKF 96365 could also enhance the sensitivity of glioma cell lines to irradiation (Ding et al., 2010), suggesting that SKF 96365 may be developed not only as an anti-chemotherapy, but also as an adjuvant drug for radiotherapy.

In summary, the antineoplastic effects of SKF 96345 are universal. However, it has been confirmed that its effects are nonspecific (Franzius et al., 1994), and therefore it is necessary to conduct more studies to clearly delineate its specific mechanisms.

2-Aminoethoxydiphenyl Borate and Analogs

2-APB (2-Diphenylboranyloxyethanamine)

Initial studies reported that 2-APB, as a novel membrane-penetrable modulator, inhibited Ca²⁺ release induced by IP₃ without affecting IP₃ binding to IP₃R (IC₅₀ = 42 µM) (Maruyama et al., 1997). Subsequently, 2-APB was found to be a reliable blocker of SOCE but an inconsistent inhibitor of IP3-induced Ca²⁺ release. With further study, it was found that 2-APB could exert both stimulatory and inhibitory effects on Ca²⁺ influx through CRAC channels: at low concentrations (1–5 µM), it activated SOCE pathway, while at high concentrations (≥10 µM), it blocked SOCE pathway completely (Prakriya and Lewis, 2001). The mechanisms of the dual effects of 2-APB on SOCE are also complicated: 2-APB could inhibit STIM1 directly by facilitating the coupling between CC1 (coiled-coil 1) and SOAR (STIM-ORAI-activating region) of STIM1. On the other hand, 2-APB could also impair the functions of STIM1 indirectly by interrupting the coupling between STIM1 and the mutant, ORAI1-V102C (Peinelt et al., 2008; Wei et al., 2016). Moreover, 2-APB could directly gate and dilate the pore diameter of ORAI1 and ORAI3 to regulate SOCE pathway without affecting STIM1 (DeHaven et al., 2008; Peinelt et al., 2008; Schindl et al., 2008; Yamashita et al., 2011; Amcheslavsky et al., 2014; Xu et al., 2016; Kappel et al., 2020). 2-APB also exerts multifaceted effects on transient receptor potential (TRP) channels (Colton and Zhu, 2007). It was reported that 2-APB could act as an agonist of TRPV1, TRPV2, TRPV3, TRPM6, and TRPC3 channels(Ma et al., 2003; Chung et al., 2004; Hu et al., 2004; Li et al., 2006), however, it exerted inhibitory roles on TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, TRPC7, TRPM2, TRPM3, TRPM7, TRPM8, TRPV3, and TRPV6 channels (Hu et al., 2004; Poburko et al., 2004; Lievremont et al., 2005; Xu et al., 2005; Li et al., 2006; Bomben and Sontheimer, 2008; Togashi et al., 2008; Chokshi et al., 2012; Kovacs et al., 2012; Singh et al., 2018). Among these TRP channels, 2-APB could close the TRPV6 channel through protein–lipid interactions by binding to TRPV6 directly, and TRPV3 also was found to undergo similar structural changes triggered by 2-APB (Singh et al., 2018; Zubcevic et al., 2018).

When used as a blocker of SOCE at high concentrations, 2-APB displayed anticancer effects on rhabdomyosarcoma (RMS), nasopharyngeal carcinoma (NPC), prostate cancer, ovarian cancer, breast cancer, glioblastoma, lung cancer, melanoma, and cervical cancer (Bomben and Sontheimer, 2008; Chen Y.-T. et al., 2013; Zeng et al., 2013; Sun et al., 2014; Leng et al., 2015; Shi et al., 2015; Schmid et al., 2016; Sun et al., 2018; Liu et al., 2020). For instance, in breast cancer, 2-APB inhibited cell viability, and proliferation through inhibiting TRPM7 channel by arresting cell cycle in S phase not by promoting cell death (Liu et al., 2020). In melanoma and cervical cancer, 2-APB could reduce migration and invasion by inhibiting actomyosin formation, invadopodium assembly and maturation, through mechanisms similar to those of SKF 96365 action (Chen Y.-T. et al., 2013; Sun et al., 2014). 2-APB in NPC could also attenuate adhesive and invasive abilities by inhibiting TRPC1 and TRPM7 (Chen et al., 2010; He et al., 2012). Furthermore, it was reported that 2-APB could effectively antagonize the angiogenesis of NPC in vivo by inhibiting VEGF production and endothelial tube formation through the blockage of SOCE (Ye et al., 2018). In another study, 2-APB sensitized NSCLC cells to the antitumor effect of bortezomib (BZM) via suppression of Ca²⁺-mediated autophagy (Qu et al., 2018).

These effects suggest that 2-APB is attractive as a potentially potent therapy for primary cancer and metastatic cancer.

2-Aminoethoxydiphenyl Borate and Analogs

As 2-APB is a promising but not entirely specific SOCE inhibitor, Goto et al. explored two novel 2-APB structurally isomeric analogs in order to develop more specific and potent SOCE inhibitors: DPB-162AE and DPB-163AE (Goto et al., 2010). These two diphenylborinate (DPB) compounds are 100-fold more potent than 2-APB, and they are able to inhibit the clustering of STIM1 and block the ORAI1 or ORAI2 activity induced by STIM1 by inactivating the SOAR domain in STIM1. In particular, DPB-162 AE could consistently inhibit endogenous SOCE regardless of whether the concentration was high or low and exerted little effect on L-type Ca²⁺ channels, TRPC channels, or Ca²⁺ pumps when exerting maximal inhibitory effect on Ca²⁺ entry (Goto et al., 2010; Hendron et al., 2014; Bittremieux et al., 2017). However, the actions of DPB-163AE are more complex, showing a similar pattern to 2-APB by activating SOCE at low concentrations and inhibiting SOCE at higher levels (Goto et al., 2010).

Moreover, similar to 2-APB, at low concentrations (∼100 nM), both DPB-162AE and DPB-163AE could facilitate Orai3 currents, and at high concentrations (>300 nM), they transiently activated ORAI3 currents and then deactivated them. DPB compounds have been proven to activate ORAI3 in a STIM1-dependent manner, but they could not change the pore diameter of ORAI3, which is different from the mechanisms of 2-APB. It is speculated that because they are larger than 2-APB, DPB compounds are unable to enter the pore of ORAI3 (Goto et al., 2010; Hendron et al., 2014). In addition, DPB-162AE was reported to provoke leakage of Ca²⁺ from the ER into the cytosol in HeLa and SU-DHL-4 cells at concentrations required for adequate SOCE inhibition (Hendron et al., 2014; Bittremieux et al., 2017).

Although there have been no studies on DPB compounds with respect to cancer treatment to date, considering the specific inhibition of SOCE, DPB compounds are expected to be developed as potential anticancer drugs.

Pyrazole Derivatives

Pyr2 (N-[4-[3,5-Bis(trifluoromethyl)pyrazol-1-yl]phenyl]-4-Methylthiadiazole-5-Carboxamide)

Pyr2, also known as BTP2 or YM-58483, was initially found to be able to inhibit SOCE, leading to impaired IL-2 production and NFAT dephosphorylation in Jurkat cells without affecting the T cell receptor (TCR) signal transduction cascade (Ishikawa et al., 2003). BTP2 also showed complicated effects on TRP channels, TRPC1, TRPC3, TRPC5, and TRPC6 channels were inhibited effectively; however, TRPM4 was activated by BTP2 at low concentrations in a dose-dependent manner. BTP-mediated facilitation of TRPM4, which is a Ca²⁺-activated cation channel that decreases Ca²⁺ influx by depolarizing lymphocytes, is the main mechanism for the suppression of cytokine release. Furthermore, it has been reported that the mechanism of inhibiting TRP channels, such as TRPC3 and TRPC5, involved in reducing their open probability rather than changing their pore properties without affecting the other Ca²⁺ signals in T cells including Ca²⁺ pumps, mitochondrial Ca²⁺ signaling and ER Ca²⁺ release (Zitt et al., 2004; He et al., 2005; Schwarz et al., 2006; Takezawa et al., 2006; Oláh et al., 2011; Wu et al., 2017).

BTP2 has exhibited inhibitory effects on several types of allergic inflammation, including autoimmune and antigen induced diseases through the suppression of cytokine release (IL-2, IL-4, IL-5, TNF-α, and IFN-γ) and T cell proliferation (Ohga et al., 2008; Law et al., 2011; Geng et al., 2012). Although many studies have indicated that BTP2 affects cancer through the modulation of immune cells, previous reports have mainly focused on the direct inhibition of cell proliferation, migration, and invasion of cancer cells themselves. For example, in colon cancer, BTP2 obviously decreased cell growth through direct SOCE inhibition (Núñez et al., 2006). BTP2 could also inhibit cell migration of cervical cancer, rhabdomyosarcoma (RMS), and breast cancer via blockage of SOCE (Chen Y.-T. et al., 2013; Schmid et al., 2016; Azimi et al., 2018); furthermore, the inhibition of cell migration in cervical cancer was due to the inhibition of actomyosin reorganization and contraction forces, similar to the effects of SKF96365 and 2-APB (Chen Y.-T. et al., 2013). It was also found that BTP2 could inhibit the proliferation and tubulogenesis of endothelial progenitor cells (EPCs), which are essential for the vascularization and metastatic switching of solid tumors (Dragoni et al., 2011; Lodola et al., 2012). On the other hand, BTP2 could inhibit the invasion of prostate cancer cells by impeding the binding of drebrin to actin filaments, with a SOCE independent mechanism (Dart et al., 2017).

In summary, the mechanism and effect of BTP2 on cancer are multi-aspect, and it is necessary to carry out further research on them for clarification.

Pyr3 (Ethyl1-(4-(2,3,3-Trichloroacrylamido)phenyl)-5-(Trifluoromethyl)-1h-Pyrazole-4-Carboxylate)

Pyr3 has mainly been recognized for directly and selectively inhibiting TRPC3 with attenuated activation of Ca²⁺-dependent signaling pathways, and structure-function relationship studies showed that the trichloroacrylic amide group is important for the TRPC3 selectivity of Pyr3 (Kiyonaka et al., 2009). The blockade of TRPC3-mediated Ca²⁺ signaling pathways by Pyr3 reduced cell proliferation, induced cell apoptosis and sensitized cell death to chemotherapeutic agents in triple-negative breast cancer through the inhibition of TRPC3-Ras GTPase-activating protein 4 (RASA4)-MAPK signaling cascade (Wang et al., 2019). In melanoma, Pyr3 also decreased the cell proliferation and migration in vitro and inhibited tumor growth in vivo by inhibiting TRPC3 and its downstream JAK/STAT5 and AKT pathways (Oda et al., 2017). Chang et al. reported that Pyr3 could inhibit the migration and invasion of glioblastoma multiforme (GBM) cells and reduce the size of tumor xenografts significantly by dephosphorylating focal adhesion kinase and myosin light chain (Chang et al., 2018). Subsequently, Pyr3 was found to effectively inhibit ORAI1-mediated SOCE in HEK293 cells and mast cells (RBL-2H3) in a dose dependent manner, and the amid-bond linked side-group pivotal for TRPC subtype selectivity was also proposed as a potential structural determinant for the SOCE inhibitory action (Schleifer et al., 2012).

Pyr6 and Pyr10 (N-[4-[3,5-Bis(trifluoromethyl)pyrazol-1-yl]phenyl]-3-Fluoropyridine-4-Carboxamide), (N-[4-[3,5-Bis(trifluoromethyl)pyrazol-1-yl]phenyl]-4-Methylbenzenesulfonamide)

It was reported that Pyr6 could inhibit both ORAI1-mediated SOCE and TRPC3 channels in mast cells leading to the suppression of mast cell activation, however, its effect on SOCE inhibition was 37-fold times that of TRPC3 inhibition, and it differed from the effect of Pyr10, which could specifically inhibit TRPC3 and had no effect on SOCE (Schleifer et al., 2012; Chauvet et al., 2016), thereby suggesting that Pyr6 and Pyr10 can be used as valuable tools to distinguish SOCE and TRPC3 channels.

GSK-5503A, GSK-7975A and GSK-5498A (2,6-Difluoro-N-[1-[(2-Phenoxyphenyl)methyl]pyrazol-3-yl]benzamide), (2,6-Difluoro-N-[1-[[4-Hydroxy-2-(trifluoromethyl)phenyl]methyl]pyrazol-3-yl]benzamide), (2,6-Difluoro-N-[1-[[2-Fluoro-6-(trifluoromethyl)phenyl]methyl]pyrazol-3-yl]benzamide)

Several novel pyrazole compounds including GSK-5503A, GSK-7975A, and GSK-5498A have been developed by GlaxoSmithKline as specific blockers of SOCE. GSK-5503A and GSK-7975A could inhibit STIM1-mediated ORAI1 and ORAI3 currents potentially via an allosteric effect on the selectivity filter of ORAI with a slow onset of action that did not have effects on STIM1-STIM1 oligomerization or STIM1-ORAI1 coupling (Yamashita et al., 2007; Derler et al., 2013). GSK-7975A could also efficiently inhibit the TRPV6 channel, possibly due to its architectural similarities to the selectivity filters of ORAI channels (Owsianik et al., 2006; Derler et al., 2013; Jairaman and Prakriya, 2013). GSK-5498A and GSK-7975A have been used to inhibit mediator and cytokine release from mast cells and T cells (such as IFN-γ and IL2) in multiple human and rat preparations by completely inhibiting SOCE (Rice et al., 2013). Although the roles of immune cells and cytokines are complicated in the tumor microenvironment, these compounds are expected to be applied as cancer treatments that function through anticancer immunity processes under certain circumstances.

Synta66 (N-[4-(2,5-Dimethoxyphenyl)phenyl]-3-Fluoropyridine-4-Carboxamide)

Synta66, also known as GSK1349571A, has garnered extensive attention in recent years because of its ability to selectively inhibit CRAC channels without affecting on PDGF- or ATP-evoked Ca²⁺ release, overexpressed TRPC5 channels, native TRPC1/5-containing channels, STIM1 clustering or nonselective store-operated cationic currents (Li et al., 2011). It has been confirmed that the potency of SOCE inhibition is directed against Orai1 in the order of Synta66 > 2-APB > GSK-7975A > SKF96365 > MRS1845 in human platelets (van Kruchten et al., 2012). By inhibiting SOCE effectively and specifically, Synta66 could inhibit the receptor-triggered mutual activation between Syk activation and Ca²⁺ influx in the RBL mast cell line, reduce the release of histamine, leukotriene C₄ (LTC₄), and cytokines (such as IL-5, IL-8, IL-13, and TNF-α) in human lung mast cells (HLMCs), and inhibit the expression of T-bet and the production of IL-2, IL17, and IFN-γ in lamina propria mononuclear cells (LPMCs) and biopsy specimens obtained from inflammatory bowel disease (IBD) patients (Ng et al., 2008; Di Sabatino et al., 2009; Ashmole et al., 2012). Azimi et al. compared the pharmacological inhibitory effects of Synta66 and BTP2 on SOCE pathway in breast cancer cell lines. They found that both Synta66 and BTP2 could inhibit the protease activated receptor 2 (PAR2) activator, and trypsin and EGF produced Ca²⁺ influx and serum-activated migration of MDA-MB-468 cells (Azimi et al., 2018). However, interestingly, Synta66, but not BTP2, had no effect on proliferation or EGF-activated cell migration, which are realized through unexplored mechanisms (Azimi et al., 2018). To date, no study has investigated whether Synta66 has anti-tumor effects in other cancers, nevertheless, Synta66 still has great potential to be developed as an available therapy for tumor treatment due to its specific and effective inhibition of SOCE.

Monoclonal Antibodies

Anti-ORAI1 Monoclonal Antibodies

Lin et al. developed high-affinity fully human mAbs to human ORAI1, that bind to amino acid residues 210–217 of the human ORAI1 extracellular loop 2 domain (ECL2). These mAbs potently inhibited the SOCE, NFAT translocation and cytokine secretion from Jurkat T cells and in human whole blood (Lin et al., 2013). Another mAb to human native ORAI1, generated by Cox, also binds to ECL2 and could block the function of T cells both in vitro and in vivo, including the inhibition of T cell proliferation and cytokine production in immune cells isolated from rheumatoid arthritis patients and showed efficacy on an anti-ORAI1 human T cell-mediated graft-versus host disease (GvHD) mouse model (Cox et al., 2013), suggesting that mAb may be a novel treatment for humans with autoimmune diseases. Taken together, since anti-ORAI1 mAbs could impact on the autoimmune response, we speculate that they also show great potential to be used as cancer therapy by modulating of the tumor immune microenvironment.

Inhibitors in Clinical Trials

Carboxyamidotriazole (5-Amino-1-[[3,5-Dichloro-4-(4-Chlorobenzoyl)phenyl]methyl]triazole-4-Carboxamide)

CAI (carboxyamidotriazole), also called L-651582, is one of the SOCE inhibitors that has been evaluated in clinical trials. It was initially developed as a coccidiostat and was confirmed to inhibit calcium influx, including SOCE, RMCE and VDCE (Hupe et al., 1991; Kohn et al., 1994; Sjaastad et al., 1996). Through the inhibition of Ca²⁺ influx and related signaling processes, such as receptor-associated tyrosine phosphorylation, arachidonic acid generation, and nucleotide biosynthesis, CAI displayed effective anticancer effects, including antiproliferative, antimigratory, antiangiogenic and antimetastatic properties, in a broad range of human tumors, including melanoma, glioblastoma, head and neck squamous cell carcinoma (HNSCC), hepatoma, small cell lung cancer (SCLC), chronic myelogenous leukemia (CML), and ovarian, breast, colon and prostate cancer (Kohn and Liotta, 1990; Kohn et al., 1992; Wasilenko et al., 1996; Jacobs et al., 1997; Wu et al., 1997; Luzzi et al., 1998; Moody et al., 2003; Enfissi et al., 2004; Corrado et al., 2011). Moreover, CAI could exert its anti-tumor activity through modulation of the tumor immune microenvironment by inhibiting proinflammatory cytokine production (such as TNF-α) in tumor-associated macrophages (TAMs), promoting IFN-γ release from activated CD8⁺ T cells or stimulating the IDO1-Kyn metabolic circuitry (Ju et al., 2012; Shi et al., 2019).

As a potential anticancer drug, CAI has been tested in phase I/II/III clinical trials, some of which showing that CAI could stabilize and improve the condition of patients with pancreaticobiliary carcinomas, melanoma, non-small cell lung cancer, epithelial ovarian cancer, prostate cancer, glioblastoma and other anaplastic gliomas while exhibiting a limited toxicity profile (Figg et al., 1995; Kohn et al., 1996; Bauer et al., 1999; Hussain et al., 2003; Hillman et al., 2010; Das, 2018; Omuro et al., 2018). However, its performance was barely satisfactory in many clinical trials, preventing it from being a first-line chemotherapy drug (Stadler et al., 2005).

RP4010

RP4010 was developed by Rhizen Pharmaceuticals. It was confirmed to block SOCE and SOCE-mediated Ca²⁺ oscillations in a dose-dependent manner, leading to the inhibition of NF-κB/p65 translocation to nuclei, thus impeding the proliferation and in ESCC xenograft tumor growth (Cui et al., 2018). In pancreatic ductal adenocarcinoma, RP4010 inhibited cancer cell proliferation and colony formation by reducing Akt/mTOR and Ca²⁺ influx-mediated NFAT signaling. Furthermore, RP4010 combined with gemcitabine and nab-paclitaxel could enhance anticancer activities in PDAC cells and patient-derived xenografts, indicating the potential of RP4010 as an anticancer chemotherapy (Khan et al., 2020). Indeed, RP4010 is in phase I/IB clinical trials currently.

CM4620 (N-[5-(6-Chloro-2,2-Difluoro-1,3-Benzodioxol-5-yl)pyrazin-2-yl]-2-Fluoro-6-Methylbenzamide)

CM4620, also called CM-128, was developed by CalciMedica and tested in phase I/II clinical trials to reduce pancreatitis. It could inhibit cell death pathway activation by SOCE inhibition in pancreatic acinar cells, thus leading to markedly reduced acute pancreatitis in mouse models (Wen et al., 2015). A recent study further demonstrated that in acute pancreatitis, CM4620 could not only inhibit the necrosis of parenchymal pancreatic acinar cells but could also prevent the activation of immune cells to reduce inflammation (Waldron et al., 2019). Although the effect of CM4620 on cancer cells is still unknown, it has the potential to be developed as a cancer therapy through its regulation of tumor immune cells.

Other Small Molecular Inhibitors

ML-9 (1-(5-chloronaphthalen-1-yl)sulfonyl-1,4-diazepane) was initially described as an inhibitor of myosin light chain kinases (MLCKs) that binds at or near the ATP-binding site at the active center of kinases with or without Ca²⁺ calmodulin (Saitoh et al., 1987). Shortly thereafter, ML-9 was found to inhibit agonist-stimulated Ca²⁺ entry in endothelial cells without affecting the release of intracellular Ca²⁺ stores (Watanabe et al., 1996), and it was confirmed to inhibit SOCE in a dose-dependent manner by blocking rearrangement and puncta formation of STIM1 without inhibiting MLCKs. Thus far, ML-9 is the only inhibitor of STIM1 translocation (Smyth et al., 2008). Furthermore, ML-9 could also inhibit the activity of TRPC5 channel by impairing its plasma membrane localization through MLCK inhibition (Shimizu et al., 2006), causing apoptosis in both untransformed and transformed epithelial cells, retarding the growth of mammary and prostate cancer cells and blocking the invasion and adhesion of human pancreatic cancer cells (Kaneko et al., 2002). In another study, ML-9 reduced SOCE and induced Ca²⁺-dependent autophagy to promote the death of prostate cancer cells, but the effect of ML-9 on autophagy was independent of STIM1 and SOCE inhibition, suggesting that ML-9 may exert its effects on cancer cells through multiple mechanisms. Moreover, ML-9 combined with docetaxel could enhance the cell death of LNCaP, PC3 and DU-145 cells, suggesting that ML-9 may be developed as an adjuvant to anticancer chemotherapy (Kondratskyi et al., 2014).

NPPB (5-nitro-2-(3-phenylpropylamino)-benzoic acid), frequently used as a blocker of chloride channels, could also reduce CCE in endothelial cells (Gericke et al., 1994). It was also confirmed that NPPB could directly interact with CRAC to reversibly inhibit Ca²⁺ influx in Jurkat cells in a dose-dependent manner (Li et al., 2000). In ovarian cancer, NPPB could significantly inhibit A2780 cell adhesion and invasion (Li et al., 2009).

AnCoA4 (3-(6-methoxy-1,3-benzodioxol-5-yl)-8,8-dimethylpyrano[2,3-f]chromen-4-one) was identified by screening small-molecule microarray (SMM) using minimal functional domains of STIM1 and ORAI1, and it was found to inhibit Ca²⁺ influx by binding to the C-terminus of ORAI1 directly to perturb the interaction between STIM1 and ORAI1 by reducing the affinity of ORAI1 for STIM1. Through SOCE inhibition, AnCoA4 blocked T cell activation and inhibited the T cell-mediated immune response in vitro and in vivo, indicting the possibility that it can be used in therapeutic areas, including immunomodulation, inflammation and cancer (Sadaghiani et al., 2014).

RO2959 (2,6-difluoro-N-[5-[4-methyl-1-(1,3-thiazol-2-yl)-3,6-dihydro-2H-pyridin-5-yl]pyrazin-2-yl]benzamide) could specifically block SOCE by inhibiting the IP3-dependent CRAC current in native RBL-2H3 cells, CHO cells with STIM1/ORAI1 overexpression and human primary CD4⁺ T cells, resulting in a decrease in TCR-triggered gene expression, cell proliferation and cytokine production in T cells (Chen G. et al., 2013).

YZ129 (4-(isoquinolin-6-ylamino)-naphthalene-1,2-dione) was identified because of its inhibition of thapsigargin-triggered Ca²⁺ influx and NFAT nuclear entry through an automated high-content screening platform and it was found to exhibit potent anti-tumor activity against glioblastoma. It could bind to HSP90 directly and antagonize its calcineurin-chaperoning effect to reduce NFAT nuclear translocation and inhibit other key proto-oncogenic pathways, including hypoxic and glycolytic pathways and the PI3K/AKT/mTOR axis, thus leading to cell cycle arrest in G2/M phase of glioblastoma and promoting apoptosis and inhibition of tumor cell proliferation and migration (Liu et al., 2019).

MRS-1844 (DHPs-32) and MRS-1845 (DHPs-35) are compounds in the 1,4-dihydropyridine (DHP) family, and they were confirmed to inhibit store-operated calcium channels and reduce voltage-dependent L-type calcium channels. In addition, their potency in SOCE inhibition was much smaller than that of common SOCE inhibitors (the reported order is Synta66 > 2-APB > GSK-7975A > SKF96365 > MRS1845) (Harper et al., 2003; van Kruchten et al., 2012).

Repurposing FDA-Approved Drugs

In addition to the abovementioned compounds targeting SOCE, other compounds that have been approved for clinical use in corresponding diseases were confirmed to inhibit SOCE. The ability of these compounds to inhibit Ca²⁺ influx through SOCE indicates the importance of learning more about their pharmacological properties and mechanisms, and the potential to extend their clinical indications.

Diethylstilbestrol (DES, 4-[(E)-4-(4-hydroxyphenyl)-hex-3-en-3-yl]-phenol) is a potent synthetic estrogen used for estrogen therapy in prostate and breast cancer. It was reported to inhibit SOCE and Ca²⁺ influx in a variety of cell types without affecting the whole-cell monovalent cation current mediated by TRPM7 channels. Trans-stilbene, a close structural analog of DES that lacks hydroxyl and ethyl groups, had no effect on CRAC current, further suggesting the specificity of DES for SOCE (Zakharov et al., 2004; Ohana et al., 2009; Dobrydneva et al., 2010).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to relieve pain, fever and inflammation. Epidemiological studies worldwide have demonstrated that NSAIDs also have cancer-protective effects, as these drugs are associated with a reduced risk of various types of cancer. In colon cancer, it has been reported that NSAIDs could exert antiproliferative effects through SOCE inhibition, and salicylate, the main aspirin metabolite, is considered a mild mitochondrial uncoupler that prevents mitochondrial Ca²⁺ uptake and promotes the Ca²⁺-dependent inactivation of SOCE, thus inhibiting the proliferation of HT29 cells (Núñez et al., 2006). Another study suggested that STIM1 overexpression promoted colorectal cancer progression through an increase in the expression of the pro-inflammatory and pro-metastatic enzyme cyclooxygenase-2 (COX-2). The inhibition of COX-2 with two NSAIDs, ibuprofen and indomethacin, abrogated STIM1-induced colorectal cancer (CRC) progression (Wang et al., 2015).

Mibefradil ([(1S,2S)-2-[2-[3-(1H-benzimidazol-2-yl)propyl-methylamino]ethyl]-6-fluoro-1-propan-2-yl-3,4-dihydro-1H-naphthalen-2-yl]2-methoxyacetate), a T-type Ca²⁺ channel blocker that was initially developed as a cardiovascular drug, was recently found to inhibit SOCE by blocking ORAI channels in a dose-dependent and reversible manner to significantly inhibit cell proliferation, induce cell apoptosis and arrest cell cycle in S and G2/M phases in HEK-293T-REx cells (Li et al., 2019).

Conclusion and Perspectives

Ca²⁺ signaling is involved in almost all cellular activities in organisms. As a major route of Ca²⁺ entry in mammalian cells for replenishing the depleted intracellular Ca²⁺ store, SOCE regulates a diverse array of biological processes. Accumulating evidence has shown that STIM/ORAI-mediated SOCE is excessive in cancer tissues, and it is becoming clear that augmented SOCE promotes the malignant behavior of cancer cells, including tumor growth, angiogenesis, and metastasis. Therefore, SOCE could be a potential therapeutic target for the treatment of cancer.

As we summarized above, multiple compounds targeting SOCE have been developed and their efficiency in the inhibition of proliferation and migration of cancer cells has been evaluated. However, rare SOCE inhibitors have been approved for clinical use in cancer treatment due to their poor selectivity, which urgently needs to addressed. In addition, as SOCE is not the only channel for Ca²⁺ entry, cells could adopt other ways to obtain sufficient Ca²⁺ even after complete SOCE inhibition. Under this condition, drug combinations could be considered. Furthermore, due to the universal roles of Ca²⁺ signaling in cells, the cytotoxicity of SOCE inhibitors on normal cells and some anticancer immune cell inhibitors should also be considered in clinical anticancer applications. Developing SOCE inhibitors that could specifically target tumor tissues in certain circumstances is a hopeful therapeutic orientation toward cancer in the future.

References

• 1

  AmcheslavskyA.SafrinaO.CahalanM. D. (2014). State-Dependent Block of Orai3 TM1 and TM3 Cysteine Mutants: Insights Into 2-APB Activation. J. Gen. Physiol.143 (5), 621–631. 10.1085/jgp.201411171

  • CrossRef
  • Google Scholar

• 2

  AmcheslavskyA.WoodM. L.YerominA. V.ParkerI.FreitesJ. A.TobiasD. J.et al (2015). Molecular Biophysics of Orai Store-Operated Ca2+ Channels. Biophys. J.108 (2), 237–246. 10.1016/j.bpj.2014.11.3473

  • CrossRef
  • Google Scholar

• 3

  Arias-MontañoJ.-A.GibsonW. J.YoungJ. M. (1998). SK&F 96365 (1-{β-[3-(4-Methoxyphenyl)propoxy]- 4-Methoxyphenylethyl}-1H-Imidazole Hydrochloride) Stimulates Phosphoinositide Hydrolysis in Human U373 MG Astrocytoma Cells. Biochem. Pharmacol.56 (8), 1023–1027. 10.1016/s0006-2952(98)00125-7

  • CrossRef
  • Google Scholar

• 4

  AshmoleI.DuffyS. M.LeylandM. L.MorrisonV. S.BeggM.BraddingP. (2012). CRACM/Orai Ion Channel Expression and Function in Human Lung Mast Cells. J. Allergy Clin. Immunol.129 (6), 1628–1635. 10.1016/j.jaci.2012.01.070

  • CrossRef
  • Google Scholar

• 5

  AzimiI.BongA. H.PooG. X. H.ArmitageK.LokD.Roberts-ThomsonS. J.et al (2018). Pharmacological Inhibition of Store-Operated Calcium Entry in MDA-MB-468 Basal A Breast Cancer Cells: Consequences on Calcium Signalling, Cell Migration and Proliferation. Cell. Mol. Life Sci.75 (24), 4525–4537. 10.1007/s00018-018-2904-y

  • CrossRef
  • Google Scholar

• 6

  BauerK. S.FiggW. D.HamiltonJ. M.JonesE. C.PremkumarA.SteinbergS. M.et al (1999). A Pharmacokinetically Guided Phase II Study of Carboxyamido-Triazole in Androgen-Independent Prostate Cancer. Clin. Cancer Res.5 (9), 2324–2329.

  • Google Scholar

• 7

  BennettB. D.AlvarezU.HruskaK. A. (2001). Receptor-Operated Osteoclast Calcium Sensing. Endocrinology142 (5), 1968–1974. 10.1210/endo.142.5.8125

  • CrossRef
  • Google Scholar

• 8

  BittremieuxM.GerasimenkoJ. V.SchuermansM.LuytenT.StapletonE.AlzayadyK. J.et al (2017). DPB162-AE, An Inhibitor of Store-Operated Ca²⁺ Entry, Can Deplete the Endoplasmic Reticulum Ca²⁺ Store. Cell Calcium62, 60–70. 10.1016/j.ceca.2017.01.015

  • CrossRef
  • Google Scholar

• 9

  BombenV. C.SontheimerH. W. (2008). Inhibition of Transient Receptor Potential Canonical Channels Impairs Cytokinesis in Human Malignant Gliomas. Cell Prolif.41 (1), 98–121. 10.1111/j.1365-2184.2007.00504.x

  • CrossRef
  • Google Scholar

• 10

  BombenV. C.SontheimerH. (2010). Disruption of Transient Receptor Potential Canonical Channel 1 Causes Incomplete Cytokinesis and Slows the Growth of Human Malignant Gliomas. Glia58 (10), 1145–1156. 10.1002/glia.20994

  • CrossRef
  • Google Scholar

• 11

  BrandmanO.LiouJ.ParkW. S.MeyerT. (2007). STIM2 is a Feedback Regulator that Stabilizes Basal Cytosolic and Endoplasmic Reticulum Ca2+ Levels. Cell131 (7), 1327–1339. 10.1016/j.cell.2007.11.039

  • CrossRef
  • Google Scholar

• 12

  CabelloO. A.SchillingW. P. (1993). Vectorial Ca2+ Flux From the Extracellular Space to the Endoplasmic Reticulum via a Restricted Cytoplasmic Compartment Regulates Inositol 1,4,5-Trisphosphate-Stimulated Ca2+ Release From Internal Stores in Vascular Endothelial Cells. Biochem. J.295 (Pt 2), 357–366. 10.1042/bj2950357

  • CrossRef
  • Google Scholar

• 13

  CaiR.DingX.ZhouK.ShiY.GeR.RenG.et al (2009). Blockade of TRPC6 Channels Induced G2/M Phase Arrest and Suppressed Growth in Human Gastric Cancer Cells. Int. J. Cancer125 (10), 2281–2287. 10.1002/ijc.24551

  • CrossRef
  • Google Scholar

• 14

  ChangH.-H.ChengY.-C.TsaiW.-C.TsaoM.-J.ChenY. (2018). Pyr3 Induces Apoptosis and Inhibits Migration in Human Glioblastoma Cells. Cell Physiol. Biochem.48 (4), 1694–1702. 10.1159/000492293

  • CrossRef
  • Google Scholar

• 15

  ChauvetS.JarvisL.ChevalletM.ShresthaN.GroschnerK.BouronA. (2016). Pharmacological Characterization of the Native Store-Operated Calcium Channels of Cortical Neurons From Embryonic Mouse Brain. Front. Pharmacol.7, 486. 10.3389/fphar.2016.00486

  • CrossRef
  • Google Scholar

• 16

  ChenJ.SandersonM. J. (2017). Store-Operated Calcium Entry is Required for Sustained Contraction and Ca2+ Oscillations of Airway Smooth Muscle. J. Physiol.595 (10), 3203–3218. 10.1113/JP272694

  • CrossRef
  • Google Scholar

• 17

  ChenJ.-P.LuanY.YouC.-X.ChenX.-H.LuoR.-C.LiR. (2010). TRPM7 Regulates the Migration of Human Nasopharyngeal Carcinoma Cell by Mediating Ca2+ Influx. Cell Calcium47 (5), 425–432. 10.1016/j.ceca.2010.03.003

  • CrossRef
  • Google Scholar

• 18

  ChenY.-F.ChiuW.-T.ChenY.-T.LinP.-Y.HuangH.-J.ChouC.-Y.et al (2011). Calcium Store Sensor Stromal-Interaction Molecule 1-Dependent Signaling Plays an Important Role in Cervical Cancer Growth, Migration, and Angiogenesis. Proc. Natl. Acad. Sci.108 (37), 15225–15230. 10.1073/pnas.1103315108

  • CrossRef
  • Google Scholar

• 19

  ChenG.PanickerS.LauK.-Y.ApparsundaramS.PatelV. A.ChenS.-L.et al (2013). Characterization of a Novel CRAC Inhibitor that Potently Blocks Human T Cell Activation and Effector Functions. Mol. Immunol.54 (3-4), 355–367. 10.1016/j.molimm.2012.12.011

  • CrossRef
  • Google Scholar

• 20

  ChenY.-T.ChenY.-F.ChiuW.-T.WangY.-K.ChangH.-C.ShenM.-R. (2013). The ER Ca2+ Sensor STIM1 Regulates Actomyosin Contractility of Migratory Cells. J. Cell Sci.126 (Pt 5), 1260–1267. 10.1242/jcs.121129

  • CrossRef
  • Google Scholar

• 21

  ChokshiR.FruasahaP.KozakJ. A. (2012). 2-Aminoethyl Diphenyl Borinate (2-APB) Inhibits TRPM7 Channels through an Intracellular Acidification Mechanism. Channels6 (5), 362–369. 10.4161/chan.21628

  • CrossRef
  • Google Scholar

• 22

  ChungS. C.McDonaldT. V.GardnerP. (1994). Inhibition by SK&F 96365 of Ca2+ Current, IL-2 Production and Activation in T Lymphocytes. Br. J. Pharmacol.113 (3), 861–868. 10.1111/j.1476-5381.1994.tb17072.x

  • CrossRef
  • Google Scholar

• 23

  ChungM.-K.LeeH.MizunoA.SuzukiM.CaterinaM. J. (2004). 2-Aminoethoxydiphenyl Borate Activates and Sensitizes the Heat-Gated Ion Channel TRPV3. J. Neurosci.24 (22), 5177–5182. 10.1523/jneurosci.0934-04.2004

  • CrossRef
  • Google Scholar

• 24

  ColtonC. K.ZhuM. X. (2007). 2-Aminoethoxydiphenyl Borate as a Common Activator of TRPV1, TRPV2, and TRPV3 Channels. Handb. Exp. Pharmacol.179, 173–187. 10.1007/978-3-540-34891-7_10

  • CrossRef
  • Google Scholar

• 25

  CorradoC.RaimondoS.FlugyA. M.FontanaS.SantoroA.StassiG.et al (2011). Carboxyamidotriazole Inhibits Cell Growth of Imatinib-Resistant Chronic Myeloid Leukaemia Cells Including T315I Bcr-Abl Mutant by a Redox-Mediated Mechanism. Cancer Lett.300 (2), 205–214. 10.1016/j.canlet.2010.10.007

  • CrossRef
  • Google Scholar

• 26

  CoxJ. H.HussellS.SøndergaardH.RoepstorffK.BuiJ.-V.DeerJ. R.et al (2013). Antibody-Mediated Targeting of the Orai1 Calcium Channel Inhibits T Cell Function. PLoS One8 (12), e82944. 10.1371/journal.pone.0082944

  • CrossRef
  • Google Scholar

• 27

  CuiC.MerrittR.FuL.PanZ. (2017). Targeting Calcium Signaling in Cancer Therapy. Acta Pharm. Sin. B7 (1), 3–17. 10.1016/j.apsb.2016.11.001

  • CrossRef
  • Google Scholar

• 28

  CuiC.ChangY.ZhangX.ChoiS.TranH.PenmetsaK. V.et al (2018). Targeting Orai1-Mediated Store-Operated Calcium Entry by RP4010 for Anti-Tumor Activity in Esophagus Squamous Cell Carcinoma. Cancer Lett.432, 169–179. 10.1016/j.canlet.2018.06.006

  • CrossRef
  • Google Scholar

• 29

  DagoC.MauxP.RoisnelT.BrigaudeauC.BekroY.-A.MignenO.et al (2018). Preliminary Structure-Activity Relationship (SAR) of a Novel Series of Pyrazole SKF-96365 Analogues as Potential Store-Operated Calcium Entry (SOCE) Inhibitors. Int. J. Mol. Sci.19 (3), 856. 10.3390/ijms19030856

  • CrossRef
  • Google Scholar

• 30

  DartA. E.WorthD. C.MuirG.ChandraA.MorrisJ. D.McKeeC.et al (2017). The Drebrin/EB3 Pathway Drives Invasive Activity in Prostate Cancer. Oncogene36 (29), 4111–4123. 10.1038/onc.2017.45

  • CrossRef
  • Google Scholar

• 31

  DasM. (2018). Carboxyamidotriazole Orotate in Glioblastoma. Lancet Oncol.19 (6), e292. 10.1016/s1470-2045(18)30347-4

  • CrossRef
  • Google Scholar

• 32

  DeHavenW. I.SmythJ. T.BoylesR. R.BirdG. S.PutneyJ. W.Jr. (2008). Complex Actions of 2-Aminoethyldiphenyl Borate on Store-Operated Calcium Entry. J. Biol. Chem.283 (28), 19265–19273. 10.1074/jbc.M801535200

  • CrossRef
  • Google Scholar

• 33

  DerlerI.SchindlR.FritschR.HeftbergerP.RiedlM. C.BeggM.et al (2013). The Action of Selective CRAC Channel Blockers is Affected by the Orai Pore Geometry. Cell Calcium53 (2), 139–151. 10.1016/j.ceca.2012.11.005

  • CrossRef
  • Google Scholar

• 34

  Di SabatinoA.RovedattiL.KaurR.SpencerJ. P.BrownJ. T.MorissetV. D.et al (2009). Targeting Gut T Cell Ca2+ Release-Activated Ca2+ Channels Inhibits T Cell Cytokine Production and T-Box Transcription Factor T-Bet in Inflammatory Bowel Disease. J. Immunol.183 (5), 3454–3462. 10.4049/jimmunol.0802887

  • CrossRef
  • Google Scholar

• 35

  DingX.HeZ.ZhouK.ChengJ.YaoH.LuD.et al (2010). Essential Role of TRPC6 Channels in G2/M Phase Transition and Development of Human Glioma. J. Natl. Cancer Inst.102 (14), 1052–1068. 10.1093/jnci/djq217

  • CrossRef
  • Google Scholar

• 36

  DobrydnevaY.WilliamsR. L.BlackmoreP. F. (2010). Diethylstilbestrol and Other Nonsteroidal Estrogens: Novel Class of Store-Operated Calcium Channel Modulators. J. Cardiovasc. Pharmacol.55 (5), 522–530. 10.1097/FJC.0b013e3181d64b33

  • CrossRef
  • Google Scholar

• 37

  DragoniS.LaforenzaU.BonettiE.LodolaF.BottinoC.Berra-RomaniR.et al (2011). Vascular Endothelial Growth Factor Stimulates Endothelial colony Forming Cells Proliferation and Tubulogenesis by Inducing Oscillations in Intracellular Ca2+ Concentration. Stem Cells29 (11), 1898–1907. 10.1002/stem.734

  • CrossRef
  • Google Scholar

• 38

  EnfissiA.PrigentS.ColosettiP.CapiodT. (2004). The Blocking of Capacitative Calcium Entry by 2-Aminoethyl Diphenylborate (2-APB) and Carboxyamidotriazole (CAI) Inhibits Proliferation in Hep G2 and Huh-7 Human Hepatoma Cells. Cell Calcium36 (6), 459–467. 10.1016/j.ceca.2004.04.004

  • CrossRef
  • Google Scholar

• 39

  FiggW. D.ColeK. A.ReedE.SteinbergS. M.PiscitelliS. C.DavisP. A.et al (1995). Pharmacokinetics of Orally Administered Carboxyamido-Triazole, an Inhibitor of Calcium-Mediated Signal Transduction. Clin. Cancer Res.1 (8), 797–803.

  • Google Scholar

• 40

  FranziusD.HothM.PennerR. (1994). Non-Specific Effects of Calcium Entry Antagonists in Mast Cells. Pflugers Arch.428 (5–6), 433–438. 10.1007/bf00374562

  • CrossRef
  • Google Scholar

• 41

  GengS.GaoY.-d.YangJ.ZouJ.-j.GuoW. (2012). Potential Role of Store-Operated Ca2+ Entry in Th2 Response Induced by Histamine in Human Monocyte-Derived Dendritic Cells. Int. Immunopharmacol.12 (2), 358–367. 10.1016/j.intimp.2011.12.008

  • CrossRef
  • Google Scholar

• 42

  GerickeM.OikeM.DroogmansG.NiliusB. (1994). Inhibition of Capacitative Ca2+ Entry by a Cl− Channel Blocker in Human Endothelial Cells. Eur. J. Pharmacol. Mol. Pharmacol.269 (3), 381–384. 10.1016/0922-4106(94)90046-9

  • CrossRef
  • Google Scholar

• 43

  GiambellucaM. S.GendeO. A. (2007). Selective Inhibition of Calcium Influx by 2-Aminoethoxydiphenyl Borate. Eur. J. Pharmacol.565 (1–3), 1–6. 10.1016/j.ejphar.2007.02.017

  • CrossRef
  • Google Scholar

• 44

  GibonJ.TuP.BouronA. (2010). Store-Depletion and Hyperforin Activate Distinct Types of Ca2+-Conducting Channels in Cortical Neurons. Cell Calcium47 (6), 538–543. 10.1016/j.ceca.2010.05.003

  • CrossRef
  • Google Scholar

• 45

  GoswameeP.PounardjianT.GiovannucciD. R. (2018). Arachidonic Acid-Induced Ca2+ Entry and Migration in a Neuroendocrine Cancer Cell Line. Cancer Cell Int.18, 30. 10.1186/s12935-018-0529-8

  • CrossRef
  • Google Scholar

• 46

  GotoJ.-I.SuzukiA. Z.OzakiS.MatsumotoN.NakamuraT.EbisuiE.et al (2010). Two Novel 2-Aminoethyl Diphenylborinate (2-APB) Analogues Differentially Activate and Inhibit Store-Operated Ca2+ Entry via STIM Proteins. Cell Calcium47 (1), 1–10. 10.1016/j.ceca.2009.10.004

  • CrossRef
  • Google Scholar

• 47

  HarperJ. L.Camerini-OteroC. S.LiA.-H.KimS.-A.JacobsonK. A.DalyJ. W. (2003). Dihydropyridines as Inhibitors of Capacitative Calcium Entry in Leukemic HL-60 Cells. Biochem. Pharmacol.65 (3), 329–338. 10.1016/s0006-2952(02)01488-0

  • CrossRef
  • Google Scholar

• 48

  HeL.-P.HewavitharanaT.SoboloffJ.SpassovaM. A.GillD. L. (2005). A Functional Link Between Store-Operated and TRPC Channels Revealed by the 3,5-Bis(trifluoromethyl)pyrazole Derivative, BTP2. J. Biol. Chem.280 (12), 10997–11006. 10.1074/jbc.M411797200

  • CrossRef
  • Google Scholar

• 49

  HeB.LiuF.RuanJ.LiA.ChenJ.LiR.et al (2012). Silencing TRPC1 Expression Inhibits Invasion of CNE2 Nasopharyngeal Tumor Cells. Oncol. Rep.27 (5), 1548–1554. 10.3892/or.2012.1695

  • CrossRef
  • Google Scholar

• 50

  HendronE.WangX.ZhouY.CaiX.GotoJ.-I.MikoshibaK.et al (2014). Potent Functional Uncoupling Between STIM1 and Orai1 by Dimeric 2-Aminodiphenyl Borinate Analogs. Cell Calcium56 (6), 482–492. 10.1016/j.ceca.2014.10.005

  • CrossRef
  • Google Scholar

• 51

  HillmanS. L.MandrekarS. J.BotB.DeMatteoR. P.PerezE. A.BallmanK. V.et al (2010). Evaluation of the Value of Attribution in the Interpretation of Adverse Event Data: A North Central Cancer Treatment Group and American College of Surgeons Oncology Group Investigation. J. Clin. Oncol.28 (18), 3002–3007. 10.1200/jco.2009.27.4282

  • CrossRef
  • Google Scholar

• 52

  HoganP. G.LewisR. S.RaoA. (2010). Molecular Basis of Calcium Signaling in Lymphocytes: STIM and ORAI. Annu. Rev. Immunol.28, 491–533. 10.1146/annurev.immunol.021908.132550

  • CrossRef
  • Google Scholar

• 53

  HuH.-Z.GuQ.WangC.ColtonC. K.TangJ.Kinoshita-KawadaM.et al (2004). 2-Aminoethoxydiphenyl Borate is a Common Activator of TRPV1, TRPV2, and TRPV3. J. Biol. Chem.279 (34), 35741–35748. 10.1074/jbc.M404164200

  • CrossRef
  • Google Scholar

• 54

  HuangH.-K.LinY.-H.ChangH.-A.LaiY.-S.ChenY.-C.HuangS.-C.et al (2020). Chemoresistant Ovarian Cancer Enhances its Migration Abilities by Increasing Store-Operated Ca2+ Entry-Mediated Turnover of Focal Adhesions. J. Biomed. Sci.27 (1), 36. 10.1186/s12929-020-00630-5

  • CrossRef
  • Google Scholar

• 55

  HupeD. J.BoltzR.CohenC. J.FelixJ.HamE.MillerD.et al (1991). The Inhibition of Receptor-Mediated and Voltage-Dependent Calcium Entry by the Antiproliferative L-651,582. J. Biol. Chem.266 (16), 10136–10142. 10.1016/s0021-9258(18)99200-8

  • CrossRef
  • Google Scholar

• 56

  HussainM. M.KotzH.MinasianL.PremkumarA.SarosyG.ReedE.et al (2003). Phase II Trial of Carboxyamidotriazole in Patients With Relapsed Epithelial Ovarian Cancer. J. Clin. Oncol.21 (23), 4356–4363. 10.1200/jco.2003.04.136

  • CrossRef
  • Google Scholar

• 57

  IshikawaJ.OhgaK.YoshinoT.TakezawaR.IchikawaA.KubotaH.et al (2003). A Pyrazole Derivative, YM-58483, Potently Inhibits Store-Operated Sustained Ca2+ Influx and IL-2 Production in T Lymphocytes. J. Immunol.170 (9), 4441–4449. 10.4049/jimmunol.170.9.4441

  • CrossRef
  • Google Scholar

• 58

  IwamuroY.MiwaS.ZhangX.-F.MinowaT.EnokiT.OkamotoY.et al (1999). Activation of Three Types of Voltage-Independent Ca2+ Channel in A7r5 Cells by Endothelin-1 as Revealed by a Novel Ca2+channel Blocker LOE 908. Br. J. Pharmacol.126 (5), 1107–1114. 10.1038/sj.bjp.0702416

  • CrossRef
  • Google Scholar

• 59

  JacobsW.MikkelsenT.SmithR.NelsonK.RosenblumM. L.KohnE. C. (1997). Inhibitory Effects of CAI in Glioblastoma Growth and Invasion. J. Neurooncol.32 (2), 93–101. 10.1023/a:1005777711567

  • CrossRef
  • Google Scholar

• 60

  JairamanA.PrakriyaM. (2013). Molecular Pharmacology of Store-Operated CRAC Channels. Channels7 (5), 402–414. 10.4161/chan.25292

  • CrossRef
  • Google Scholar

• 61

  JingZ.SuiX.YaoJ.XieJ.JiangL.ZhouY.et al (2016). SKF-96365 Activates Cytoprotective Autophagy to Delay Apoptosis in Colorectal Cancer Cells Through Inhibition of the Calcium/CaMKIIγ/AKT-Mediated Pathway. Cancer Lett.372 (2), 226–238. 10.1016/j.canlet.2016.01.006

  • CrossRef
  • Google Scholar

• 62

  JuR.WuD.GuoL.LiJ.YeC.ZhangD. (2012). Inhibition of Pro-Inflammatory Cytokines in Tumour Associated Macrophages is a Potential Anti-Cancer Mechanism of Carboxyamidotriazole. Eur. J. Cancer48 (7), 1085–1095. 10.1016/j.ejca.2011.06.050

  • CrossRef
  • Google Scholar

• 63

  KanekoK.SatohK.MasamuneA.SatohA.ShimosegawaT. (2002). Myosin Light Chain Kinase Inhibitors Can Block Invasion and Adhesion of Human Pancreatic Cancer Cell Lines. Pancreas24 (1), 34–41. 10.1097/00006676-200201000-00005

  • CrossRef
  • Google Scholar

• 64

  KappelS.KilchT.BaurR.LochnerM.PeineltC. (2020). The Number and Position of Orai3 Units Within Heteromeric Store-Operated Ca2+ Channels Alter the Pharmacology of ICRAC. Int. J. Mol. Sci.21 (7), 2458. 10.3390/ijms21072458

  • CrossRef
  • Google Scholar

• 65

  KhanH. Y.MpillaG. B.SextonR.ViswanadhaS.PenmetsaK. V.AboukameelA.et al (2020). Calcium Release-Activated Calcium (CRAC) Channel Inhibition Suppresses Pancreatic Ductal Adenocarcinoma Cell Proliferation and Patient-Derived Tumor Growth. Cancers12 (3), 750. 10.3390/cancers12030750

  • CrossRef
  • Google Scholar

• 66

  KimJ.-H.LkhagvadorjS.LeeM.-R.HwangK.-H.ChungH. C.JungJ. H.et al (2014). Orai1 and STIM1 are Critical for Cell Migration and Proliferation of Clear Cell Renal Cell Carcinoma. Biochem. Biophys. Res. Commun.448 (1), 76–82. 10.1016/j.bbrc.2014.04.064

  • CrossRef
  • Google Scholar

• 67

  KiyonakaS.KatoK.NishidaM.MioK.NumagaT.SawaguchiY.et al (2009). Selective and Direct Inhibition of TRPC3 Channels Underlies Biological Activities of a Pyrazole Compound. Proc. Natl. Acad. Sci.106 (13), 5400–5405. 10.1073/pnas.0808793106

  • CrossRef
  • Google Scholar

• 68

  KohnE. C.LiottaL. A. (1990). L651582: A Novel Antiproliferative and Antimetastasis Agent. J. Natl. Cancer Inst.82 (1), 54–61. 10.1093/jnci/82.1.54

  • CrossRef
  • Google Scholar

• 69

  KohnE. C.SandeenM. A.LiottaL. A. (1992). In Vivo Efficacy of a Novel Inhibitor of Selected Signal Transduction Pathways Including Calcium, Arachidonate, and Inositol Phosphates. Cancer Res.52 (11), 3208–3212.

  • Google Scholar

• 70

  KohnE. C.FelderC. C.JacobsW.HolmesK. A.DayA.FreerR.et al (1994). Structure-Function Analysis of Signal and Growth Inhibition by Carboxyamido-Triazole, CAI. Cancer Res.54 (4), 935–942.

  • Google Scholar

• 71

  KohnE. C.ReedE.SarosyG.ChristianM.LinkC. J.ColeK.et al (1996). Clinical Investigation of a Cytostatic Calcium Influx Inhibitor in Patients With Refractory Cancers. Cancer Res.56 (3), 569–573.

  • Google Scholar

• 72

  KondratskyiA.YassineM.SlomiannyC.KondratskaK.GordienkoD.DewaillyE.et al (2014). Identification of ML-9 as a Lysosomotropic Agent Targeting Autophagy and Cell Death. Cell Death Dis.5 (4), e1193. 10.1038/cddis.2014.156

  • CrossRef
  • Google Scholar

• 73

  KovacsG.MontalbettiN.SimoninA.DankoT.BalazsB.ZsemberyA.et al (2012). Inhibition of the Human Epithelial Calcium Channel TRPV6 by 2-Aminoethoxydiphenyl Borate (2-APB). Cell Calcium52 (6), 468–480. 10.1016/j.ceca.2012.08.005

  • CrossRef
  • Google Scholar

• 74

  LawM.MoralesJ. L.MottramL. F.IyerA.PetersonB. R.AugustA. (2011). Structural Requirements for the Inhibition of Calcium Mobilization and Mast Cell Activation by the Pyrazole Derivative BTP2. Int. J. Biochem. Cell Biol.43 (8), 1228–1239. 10.1016/j.biocel.2011.04.016

  • CrossRef
  • Google Scholar

• 75

  LeeY. S.SayeedM. M.WursterR. D. (1993). Inhibition of Human Brain Tumor Cell Growth by a Receptor-Operated Ca2+ Channel Blocker. Cancer Lett.72 (1–2), 77–81. 10.1016/0304-3835(93)90014-z

  • CrossRef
  • Google Scholar

• 76

  LengT.-D.LiM.-H.ShenJ.-F.LiuM.-L.LiX.-B.SunH.-W.et al (2015). Suppression of TRPM7 Inhibits Proliferation, Migration, and Invasion of Malignant Human Glioma Cells. CNS Neurosci. Ther.21 (3), 252–261. 10.1111/cns.12354

  • CrossRef
  • Google Scholar

• 77

  LiJ. H.SpenceK. T.DargisP. G.ChristianE. P. (2000). Properties of Ca(2+) Release-Activated Ca(2+) Channel Block by 5-Nitro-2-(3-Phenylpropylamino)-Benzoic Acid in Jurkat Cells. Eur. J. Pharmacol.394 (2–3), 171–179. 10.1016/s0014-2999(00)00144-8

  • CrossRef
  • Google Scholar

• 78

  LiM.JiangJ.YueL. (2006). Functional Characterization of Homo- and Heteromeric Channel Kinases TRPM6 and TRPM7. J. Gen. Physiol.127 (5), 525–537. 10.1085/jgp.200609502

  • CrossRef
  • Google Scholar

• 79

  LiM.WangQ.LinW.WangB. (2009). Regulation of Ovarian Cancer Cell Adhesion and Invasion by Chloride Channels. Int. J. Gynecol. Cancer19 (4), 526–530. 10.1111/IGC.0b013e3181a3d6d2

  • CrossRef
  • Google Scholar

• 80

  LiJ.McKeownL.OjelabiO.StaceyM.FosterR.O'ReganD.et al (2011). Nanomolar Potency and Selectivity of a Ca2+ Release-Activated Ca2+ Channel Inhibitor Against Store-Operated Ca2+ Entry and Migration of Vascular Smooth Muscle Cells. Br. J. Pharmacol.164 (2), 382–393. 10.1111/j.1476-5381.2011.01368.x

  • CrossRef
  • Google Scholar

• 81

  LiP.RubaiyH. N.ChenG. L.HallettT.ZaibiN.ZengB.et al (2019). Mibefradil, a T‐Type Ca 2+ Channel Blocker Also Blocks Orai Channels by Action at the Extracellular Surface. Br. J. Pharmacol.176 (19), 3845–3856. 10.1111/bph.14788

  • CrossRef
  • Google Scholar

• 82

  LievremontJ.-P.BirdG. S.PutneyJ. W.Jr. (2005). Mechanism of Inhibition of TRPC Cation Channels by 2-Aminoethoxydiphenylborane. Mol. Pharmacol.68 (3), 758–762. 10.1124/mol.105.012856

  • CrossRef
  • Google Scholar

• 83

  LinF.-F.ElliottR.ColomberoA.GaidaK.KelleyL.MoksaA.et al (2013). Generation and Characterization of Fully Human Monoclonal Antibodies Against Human Orai1 for Autoimmune Disease. J. Pharmacol. Exp. Ther.345 (2), 225–238. 10.1124/jpet.112.202788

  • CrossRef
  • Google Scholar

• 84

  LiouJ.KimM. L.Do HeoW.JonesJ. T.MyersJ. W.FerrellJ. E.Jr.et al (2005). STIM is a Ca2+ Sensor Essential for Ca2+-Store-Depletion-Triggered Ca2+ Influx. Curr. Biol.15 (13), 1235–1241. 10.1016/j.cub.2005.05.055

  • CrossRef
  • Google Scholar

• 85

  LisA.PeineltC.BeckA.ParvezS.Monteilh-ZollerM.FleigA.et al (2007). CRACM1, CRACM2, and CRACM3 are Store-Operated Ca2+ Channels With Distinct Functional Properties. Curr. Biol.17 (9), 794–800. 10.1016/j.cub.2007.03.065

  • CrossRef
  • Google Scholar

• 86

  LiuH.HughesJ. D.RollinsS.ChenB.PerkinsE. (2011). Calcium Entry via ORAI1 Regulates Glioblastoma Cell Proliferation and Apoptosis. Exp. Mol. Pathol.91 (3), 753–760. 10.1016/j.yexmp.2011.09.005

  • CrossRef
  • Google Scholar

• 87

  LiuZ.LiH.HeL.XiangY.TianC.LiC.et al (2019). Discovery of Small-Molecule Inhibitors of the HSP90-Calcineurin-NFAT Pathway Against Glioblastoma. Cel Chem. Biol.26 (3), 352–365. 10.1016/j.chembiol.2018.11.009

  • CrossRef
  • Google Scholar

• 88

  LiuH.DilgerJ. P.LinJ. (2020). The Role of Transient Receptor Potential Melastatin 7 (TRPM7) in Cell Viability: A Potential Target to Suppress Breast Cancer Cell Cycle. Cancers12 (1), 131. 10.3390/cancers12010131

  • CrossRef
  • Google Scholar

• 89

  LodolaF.LaforenzaU.BonettiE.LimD.DragoniS.BottinoC.et al (2012). Store-Operated Ca2+ Entry is Remodelled and Controls In Vitro Angiogenesis in Endothelial Progenitor Cells Isolated From Tumoral Patients. PLoS One7 (9), e42541. 10.1371/journal.pone.0042541

  • CrossRef
  • Google Scholar

• 90

  LuzziK. J.VargheseH. J.MacDonaldI. C.SchmidtE. E.KohnE. C.MorrisV. L.et al (1998). Inhibition of Angiogenesis in Liver Metastases by Carboxyamidotriazole (CAI). Angiogenesis2 (4), 373–379. 10.1023/a:1009259521092

  • CrossRef
  • Google Scholar

• 91

  MaH.-T.VenkatachalamK.Rys-SikoraK. E.HeL.-P.ZhengF.GillD. L. (2003). Modification of Phospholipase C-γ-Induced Ca2+ Signal Generation by 2-Aminoethoxydiphenyl Borate. Biochem. J.376 (Pt 3), 667–676. 10.1042/bj20031345

  • CrossRef
  • Google Scholar

• 92

  MaJ.McCarlC.-A.KhalilS.LüthyK.FeskeS. (2010). T-Cell-Specific Deletion of STIM1 and STIM2 Protects Mice From EAE by Impairing the Effector Functions of Th1 and Th17 Cells. Eur. J. Immunol.40 (11), 3028–3042. 10.1002/eji.201040614

  • CrossRef
  • Google Scholar

• 93

  MaruyamaT.KanajiT.NakadeS.KannoT.MikoshibaK. (1997). 2APB, 2-Aminoethoxydiphenyl Borate, a Membrane-Penetrable Modulator of Ins(1,4,5)P3-Induced Ca2+ Release. J. Biochem.122 (3), 498–505. 10.1093/oxfordjournals.jbchem.a021780

  • CrossRef
  • Google Scholar

• 94

  McGahonM. K.McKeeJ.DashD. P.BrownE.SimpsonD. A.CurtisT. M.et al (2012). Pharmacological Profiling of Store-Operated Ca2+ Entry in Retinal Arteriolar Smooth Muscle. Microcirculation19 (7), 586–597. 10.1111/j.1549-8719.2012.00192.x

  • CrossRef
  • Google Scholar

• 95

  MehrotraP.SturekM.NeyraJ. A.BasileD. P. (2019). Calcium Channel Orai1 Promotes Lymphocyte IL-17 Expression and Progressive Kidney Injury. J. Clin. Invest.129 (11), 4951–4961. 10.1172/jci126108

  • CrossRef
  • Google Scholar

• 96

  MercerJ. C.DehavenW. I.SmythJ. T.WedelB.BoylesR. R.BirdG. S.et al (2006). Large Store-Operated Calcium Selective Currents Due to Co-expression of Orai1 or Orai2 With the Intracellular Calcium Sensor, Stim1. J. Biol. Chem.281 (34), 24979–24990. 10.1074/jbc.M604589200

  • CrossRef
  • Google Scholar

• 97

  MerrittJ. E.ArmstrongW. P.BenhamC. D.HallamT. J.JacobR.Jaxa-ChamiecA.et al (1990). SK&F 96365, a Novel Inhibitor of Receptor-Mediated Calcium Entry. Biochem. J.271 (2), 515–522. 10.1042/bj2710515

  • CrossRef
  • Google Scholar

• 98

  MoodyT. W.ChilesJ.MoodyE.SieczkiewiczG. J.KohnE. C. (2003). CAI Inhibits the Growth of Small Cell Lung Cancer Cells. Lung Cancer39 (3), 279–288. 10.1016/s0169-5002(02)00525-1

  • CrossRef
  • Google Scholar

• 99

  MotianiR. K.Hyzinski-GarcíaM. C.ZhangX.HenkelM. M.AbdullaevI. F.KuoY.-H.et al (2013). STIM1 and Orai1 Mediate CRAC Channel Activity and are Essential for Human Glioblastoma Invasion. Pflugers Arch.465 (9), 1249–1260. 10.1007/s00424-013-1254-8

  • CrossRef
  • Google Scholar

• 100

  NgS. W.di CapiteJ.SingaraveluK.ParekhA. B. (2008). Sustained Activation of the Tyrosine Kinase Syk by Antigen in Mast Cells Requires Local Ca2+ Influx through Ca2+ Release-Activated Ca2+ Channels. J. Biol. Chem.283 (46), 31348–31355. 10.1074/jbc.M804942200

  • CrossRef
  • Google Scholar

• 101

  NordströmT.NevanlinnaH. A.AnderssonL. C. (1992). Mitosis-Arresting Effect of the Calcium Channel Inhibitor SK&F 96365 on Human Leukemia Cells. Exp. Cell Res.202 (2), 487–494. 10.1016/0014-4827(92)90103-f

  • CrossRef
  • Google Scholar

• 102

  NúñezL.ValeroR. A.SenovillaL.Sanz-BlascoS.García-SanchoJ.VillalobosC. (2006). Cell Proliferation Depends on Mitochondrial Ca2+ Uptake: Inhibition by Salicylate. J. Physiol.571 (Pt 1), 57–73. 10.1113/jphysiol.2005.100586

  • CrossRef
  • Google Scholar

• 103

  OdaK.UmemuraM.NakakajiR.TanakaR.SatoI.NagasakoA.et al (2017). Transient Receptor Potential Cation 3 Channel Regulates Melanoma Proliferation and Migration. J. Physiol. Sci.67 (4), 497–505. 10.1007/s12576-016-0480-1

  • CrossRef
  • Google Scholar

• 104

  OhanaL.NewellE. W.StanleyE. F.SchlichterL. C. (2009). The Ca2+ Release-Activated Ca2+ Current (ICRAC) Mediates Store-Operated Ca2+ Entry in Rat Microglia. Channels3 (2), 129–139. 10.4161/chan.3.2.8609

  • CrossRef
  • Google Scholar

• 105

  OhgaK.TakezawaR.ArakidaY.ShimizuY.IshikawaJ. (2008). Characterization of YM-58483/BTP2, a Novel Store-Operated Ca2+ Entry Blocker, on T Cell-Mediated Immune Responses In Vivo. Int. Immunopharmacol.8 (13–14), 1787–1792. 10.1016/j.intimp.2008.08.016

  • CrossRef
  • Google Scholar

• 106

  OláhT.FodorJ.RuzsnavszkyO.VinczeJ.BerbeyC.AllardB.et al (2011). Overexpression of Transient Receptor Potential Canonical Type 1 (TRPC1) Alters Both Store Operated Calcium Entry and Depolarization-Evoked Calcium Signals in C2C12 Cells. Cell Calcium49 (6), 415–425. 10.1016/j.ceca.2011.03.012

  • CrossRef
  • Google Scholar

• 107

  OmuroA.BealK.McNeillK.YoungR. J.ThomasA.LinX.et al (2018). Multicenter Phase IB Trial of Carboxyamidotriazole Orotate and Temozolomide for Recurrent and Newly Diagnosed Glioblastoma and Other Anaplastic Gliomas. J. Clin. Oncol.36 (17), 1702–1709. 10.1200/jco.2017.76.9992

  • CrossRef
  • Google Scholar

• 108

  OwsianikG.D'hoedtD.VoetsT.NiliusB. (2006). Structure-Function Relationship of the TRP Channel Superfamily. Rev. Physiol. Biochem. Pharmacol.156, 61–90.

  • Google Scholar

• 109

  OzakiS.SuzukiA. Z.BauerP. O.EbisuiE.MikoshibaK. (2013). 2-Aminoethyl Diphenylborinate (2-APB) Analogues: Regulation of Ca2+ Signaling. Biochem. Biophysical Res. Commun.441 (2), 286–290. 10.1016/j.bbrc.2013.08.102

  • CrossRef
  • Google Scholar

• 110

  ParkC. Y.HooverP. J.MullinsF. M.BachhawatP.CovingtonE. D.RaunserS.et al (2009). STIM1 Clusters and Activates CRAC Channels via Direct Binding of a Cytosolic Domain to Orai1. Cell136 (5), 876–890. 10.1016/j.cell.2009.02.014

  • CrossRef
  • Google Scholar

• 111

  PeineltC.VigM.KoomoaD. L.BeckA.NadlerM. J. S.Koblan-HubersonM.et al (2006). Amplification of CRAC Current by STIM1 and CRACM1 (Orai1). Nat. Cell Biol.8 (7), 771–773. 10.1038/ncb1435

  • CrossRef
  • Google Scholar

• 112

  PeineltC.LisA.BeckA.FleigA.PennerR. (2008). 2-Aminoethoxydiphenyl Borate Directly Facilitates and Indirectly Inhibits STIM1-Dependent Gating of CRAC Channels. J. Physiol.586 (13), 3061–3073. 10.1113/jphysiol.2008.151365

  • CrossRef
  • Google Scholar

• 113

  PoburkoD.LhoteP.SzadoT.BehraT.RahimianR.McManusB.et al (2004). Basal Calcium Entry in Vascular Smooth Muscle. Eur. J. Pharmacol.505 (1–3), 19–29. 10.1016/j.ejphar.2004.09.060

  • CrossRef
  • Google Scholar

• 114

  PrakriyaM.LewisR. S. (2001). Potentiation and Inhibition of Ca(2+) Release‐Activated Ca(2+) Channels by 2‐Aminoethyldiphenyl Borate (2‐APB) Occurs Independently of IP(3) Receptors. J. Physiol.536 (Pt 1), 3–19. 10.1111/j.1469-7793.2001.t01-1-00003.x

  • CrossRef
  • Google Scholar

• 115

  PrakriyaM.LewisR. S. (2015). Store-Operated Calcium Channels. Physiol. Rev.95 (4), 1383–1436. 10.1152/physrev.00020.2014

  • CrossRef
  • Google Scholar

• 116

  QuY. Q.Gordillo-MartinezF.LawB. Y. K.HanY.WuA.ZengW.et al (2018). 2-Aminoethoxydiphenylborane Sensitizes Anti-Tumor Effect of Bortezomib via Suppression of Calcium-Mediated Autophagy. Cell Death Dis.9 (3), 361. 10.1038/s41419-018-0397-0

  • CrossRef
  • Google Scholar

• 117

  RiceL. V.BaxH. J.RussellL. J.BarrettV. J.WaltonS. E.DeakinA. M.et al (2013). Characterization of Selective Calcium-Release Activated Calcium Channel Blockers in Mast Cells and T-Cells From Human, Rat, Mouse and Guinea-Pig Preparations. Eur. J. Pharmacol.704 (1-3), 49–57. 10.1016/j.ejphar.2013.02.022

  • CrossRef
  • Google Scholar

• 118

  RoosJ.DiGregorioP. J.YerominA. V.OhlsenK.LioudynoM.ZhangS.et al (2005). STIM1, an Essential and Conserved Component of Store-Operated Ca2+ Channel Function. J. Cell Biol.169 (3), 435–445. 10.1083/jcb.200502019

  • CrossRef
  • Google Scholar

• 119

  SadaghianiA. M.LeeS. M.OdegaardJ. I.Leveson-GowerD. B.McPhersonO. M.NovickP.et al (2014). Identification of Orai1 Channel Inhibitors by Using Minimal Functional Domains to Screen Small Molecule Microarrays. Chem. Biol.21 (10), 1278–1292. 10.1016/j.chembiol.2014.08.016

  • CrossRef
  • Google Scholar

• 120

  SaitohM.IshikawaT.MatsushimaS.NakaM.HidakaH. (1987). Selective Inhibition of Catalytic Activity of Smooth Muscle Myosin Light Chain Kinase. J. Biol. Chem.262 (16), 7796–7801. 10.1016/s0021-9258(18)47638-7

  • CrossRef
  • Google Scholar

• 121

  SchindlR.BergsmannJ.FrischaufI.DerlerI.FahrnerM.MuikM.et al (2008). 2-Aminoethoxydiphenyl Borate Alters Selectivity of Orai3 Channels by Increasing Their Pore Size. J. Biol. Chem.283 (29), 20261–20267. 10.1074/jbc.M803101200

  • CrossRef
  • Google Scholar

• 122

  SchleiferH.DoleschalB.LichteneggerM.OppenriederR.DerlerI.FrischaufI.et al (2012). Novel Pyrazole Compounds for Pharmacological Discrimination Between Receptor‐Operated and Store‐Operated Ca 2+ Entry Pathways. Br. J. Pharmacol.167 (8), 1712–1722. 10.1111/j.1476-5381.2012.02126.x

  • CrossRef
  • Google Scholar

• 123

  SchmidE.StagnoM. J.YanJ.StournarasC.LangF.FuchsJ.et al (2016). Store-Operated Ca2+ Entry in Rhabdomyosarcoma Cells. Biochem. Biophys. Res. Commun.477 (1), 129–136. 10.1016/j.bbrc.2016.06.032

  • CrossRef
  • Google Scholar

• 124

  SchwarzE. C.WissenbachU.NiemeyerB. A.StraussB.PhilippS. E.FlockerziV.et al (2006). TRPV6 Potentiates Calcium-Dependent Cell Proliferation. Cell Calcium39 (2), 163–173. 10.1016/j.ceca.2005.10.006

  • CrossRef
  • Google Scholar

• 125

  SelvarajS.SunY.SukumaranP.SinghB. B. (2016). Resveratrol Activates Autophagic Cell Death in Prostate Cancer Cells via Downregulation of STIM1 and the mTOR Pathway. Mol. Carcinog.55 (5), 818–831. 10.1002/mc.22324

  • CrossRef
  • Google Scholar

• 126

  ShapovalovG.RitaineA.SkrymaR.PrevarskayaN. (2016). Role of TRP Ion Channels in Cancer and Tumorigenesis. Semin. Immunopathol.38 (3), 357–369. 10.1007/s00281-015-0525-1

  • CrossRef
  • Google Scholar

• 127

  ShawP. J.WeidingerC.VaethM.LuethyK.KaechS. M.FeskeS. (2014). CD4+ and CD8+ T Cell-Dependent Antiviral Immunity Requires STIM1 and STIM2. J. Clin. Invest.124 (10), 4549–4563. 10.1172/JCI76602

  • CrossRef
  • Google Scholar

• 128

  ShiZ.-x.RaoW.WangH.WangN.-d.SiJ.-W.ZhaoJ.et al (2015). Modeled Microgravity Suppressed Invasion and Migration of Human Glioblastoma U87 Cells Through Downregulating Store-Operated Calcium Entry. Biochem. Biophys. Res. Commun.457 (3), 378–384. 10.1016/j.bbrc.2014.12.120

  • CrossRef
  • Google Scholar

• 129

  ShiJ.ChenC.JuR.WangQ.LiJ.GuoL.et al (2019). Carboxyamidotriazole Combined With IDO1-Kyn-AhR Pathway Inhibitors Profoundly Enhances Cancer Immunotherapy. J. Immunother. Cancer7 (1), 246. 10.1186/s40425-019-0725-7

  • CrossRef
  • Google Scholar

• 130

  ShimizuS.YoshidaT.WakamoriM.IshiiM.OkadaT.TakahashiM.et al (2006). Ca2+-Calmodulin-Dependent Myosin Light Chain Kinase is Essential for Activation of TRPC5 Channels Expressed in HEK293 Cells. J. Physiol.570 (Pt 2), 219–235. 10.1113/jphysiol.2005.097998

  • CrossRef
  • Google Scholar

• 131

  SinghA. K.SaotomeK.McGoldrickL. L.SobolevskyA. I. (2018). Structural Bases of TRP Channel TRPV6 Allosteric Modulation by 2-APB. Nat. Commun.9 (1), 2465. 10.1038/s41467-018-04828-y

  • CrossRef
  • Google Scholar

• 132

  SjaastadM. D.LewisR. S.NelsonW. J. (1996). Mechanisms of Integrin-Mediated Calcium Signaling in MDCK Cells: Regulation of Adhesion by IP3- and Store-Independent Calcium Influx. Mol. Biol. Cell7 (7), 1025–1041. 10.1091/mbc.7.7.1025

  • CrossRef
  • Google Scholar

• 133

  SmythJ. T.DehavenW. I.BirdG. S.PutneyJ. W.Jr. (2008). Ca2+-Store-Dependent and -Independent Reversal of Stim1 Localization and Function. J. Cell Sci.121 (Pt 6), 762–772. 10.1242/jcs.023903

  • CrossRef
  • Google Scholar

• 134

  SongM.ChenD.YuS. P. (2014). The TRPC Channel Blocker SKF 96365 Inhibits Glioblastoma Cell Growth by Enhancing Reverse Mode of the Na+/Ca2+ Exchanger and Increasing Intracellular Ca2+. Br. J. Pharmacol.171 (14), 3432–3447. 10.1111/bph.12691

  • CrossRef
  • Google Scholar

• 135

  SpeddingM. (1982). Assessment of “Ca2+ -Antagonist” Effects of Drugs in K+ -Depolarized Smooth Muscle. Differentiation of Antagonist Subgroups. Naunyn Schmiedebergs Arch. Pharmacol.318 (3), 234–240. 10.1007/bf00500485

  • CrossRef
  • Google Scholar

• 136

  StadlerW. M.RosnerG.SmallE.HollisD.RiniB.ZaentzS. D.et al (2005). Successful Implementation of the Randomized Discontinuation Trial Design: An Application to the Study of the Putative Antiangiogenic Agent Carboxyaminoimidazole in Renal Cell Carcinoma-CALGB 69901. J. Clin. Oncol.23 (16), 3726–3732. 10.1200/jco.2005.44.150

  • CrossRef
  • Google Scholar

• 137

  SunJ.LuF.HeH.ShenJ.MessinaJ.MathewR.et al (2014). STIM1- and Orai1-Mediated Ca2+ Oscillation Orchestrates Invadopodium Formation and Melanoma Invasion. J. Cell Biol.207 (4), 535–548. 10.1083/jcb.201407082

  • CrossRef
  • Google Scholar

• 138

  SunY.SchaarA.SukumaranP.DhasarathyA.SinghB. B. (2018). TGFβ-Induced Epithelial-to-Mesenchymal Transition in Prostate Cancer Cells is Mediated via TRPM7 Expression. Mol. Carcinog.57 (6), 752–761. 10.1002/mc.22797

  • CrossRef
  • Google Scholar

• 139

  SuzukiA. Z.OzakiS.GotoJ.-I.MikoshibaK. (2010). Synthesis of Bisboron Compounds and Their Strong Inhibitory Activity on Store-Operated Calcium Entry. Bioorg. Med. Chem. Lett.20 (4), 1395–1398. 10.1016/j.bmcl.2009.12.108

  • CrossRef
  • Google Scholar

• 140

  TajeddineN.GaillyP. (2012). TRPC1 Protein Channel is Major Regulator of Epidermal Growth Factor Receptor Signaling. J. Biol. Chem.287 (20), 16146–16157. 10.1074/jbc.M112.340034

  • CrossRef
  • Google Scholar

• 141

  TakezawaR.ChengH.BeckA.IshikawaJ.LaunayP.KubotaH.et al (2006). A Pyrazole Derivative Potently Inhibits Lymphocyte Ca2+ Influx and Cytokine Production by Facilitating Transient Receptor Potential Melastatin 4 Channel Activity. Mol. Pharmacol.69 (4), 1413–1420. 10.1124/mol.105.021154

  • CrossRef
  • Google Scholar

• 142

  TiruppathiC.FreichelM.VogelS. M.PariaB. C.MehtaD.FlockerziV.et al (2002). Impairment of Store-Operated Ca2+ Entry in TRPC4(−/−) Mice Interferes With Increase in Lung Microvascular Permeability. Circ. Res.91 (1), 70–76. 10.1161/01.res.0000023391.40106.a8

  • CrossRef
  • Google Scholar

• 143

  TogashiK.InadaH.TominagaM. (2008). Inhibition of the Transient Receptor Potential Cation Channel TRPM2 by 2-Aminoethoxydiphenyl Borate (2-APB). Br. J. Pharmacol.153 (6), 1324–1330. 10.1038/sj.bjp.0707675

  • CrossRef
  • Google Scholar

• 144

  UmemuraM.BaljinnyamE.FeskeS.De LorenzoM. S.XieL.-H.FengX.et al (2014). Store-Operated Ca2+ Entry (SOCE) Regulates Melanoma Proliferation and Cell Migration. PLoS One9 (2), e89292. 10.1371/journal.pone.0089292

  • CrossRef
  • Google Scholar

• 145

  van KruchtenR.BraunA.FeijgeM. A. H.KuijpersM. J. E.Rivera-GaldosR.KraftP.et al (2012). Antithrombotic Potential of Blockers of Store-Operated Calcium Channels in Platelets. Arterioscler Thromb. Vasc. Biol.32 (7), 1717–1723. 10.1161/atvbaha.111.243907

  • CrossRef
  • Google Scholar

• 146

  VenkatachalamK.MontellC. (2007). TRP Channels. Annu. Rev. Biochem.76, 387–417. 10.1146/annurev.biochem.75.103004.142819

  • CrossRef
  • Google Scholar

• 147

  VigM.PeineltC.BeckA.KoomoaD. L.RabahD.Koblan-HubersonM.et al (2006). CRACM1 is a Plasma Membrane Protein Essential for Store-Operated Ca2+ Entry. Science312 (5777), 1220–1223. 10.1126/science.1127883

  • CrossRef
  • Google Scholar

• 148

  WaldronR. T.ChenY.PhamH.GoA.SuH. Y.HuC.et al (2019). The Orai Ca2+ Channel Inhibitor CM4620 Targets Both Parenchymal and Immune Cells to Reduce Inflammation in Experimental Acute Pancreatitis. J. Physiol.597 (12), 3085–3105. 10.1113/jp277856

  • CrossRef
  • Google Scholar

• 149

  WangX.PluznickJ. L.WeiP.PadanilamB. J.SansomS. C. (2004). TRPC4 Forms Store-Operated Ca2+ Channels in Mouse Mesangial Cells. Am. J. Physiol. Cell Physiol.287 (2), C357–C364. 10.1152/ajpcell.00068.2004

  • CrossRef
  • Google Scholar

• 150

  WangX.WangY.ZhouY.HendronE.MancarellaS.AndrakeM. D.et al (2014). Distinct Orai-Coupling Domains in STIM1 and STIM2 Define the Orai-Activating Site. Nat. Commun.5, 3183. 10.1038/ncomms4183

  • CrossRef
  • Google Scholar

• 151

  WangJ.-Y.SunJ.HuangM.-Y.WangY.-S.HouM.-F.SunY.et al (2015). STIM1 Overexpression Promotes Colorectal Cancer Progression, Cell Motility and COX-2 Expression. Oncogene34 (33), 4358–4367. 10.1038/onc.2014.366

  • CrossRef
  • Google Scholar

• 152

  WangW.RenY.WangL.ZhaoW.DongX.PanJ.et al (2018). Orai1 and Stim1 Mediate the Majority of Store-Operated Calcium Entry in Multiple Myeloma and Have Strong Implications for Adverse Prognosis. Cel. Physiol. Biochem.48 (6), 2273–2285. 10.1159/000492645

  • CrossRef
  • Google Scholar

• 153

  WangY.HeJ.JiangH.ZhangQ.YangH.XuX.et al (2018). Nicotine Enhances Store Operated Calcium Entry by Upregulating HIF 1α and SOCC Components in Non Small Cell Lung Cancer Cells. Oncol. Rep.40 (4), 2097–2104. 10.3892/or.2018.6580

  • CrossRef
  • Google Scholar

• 154

  WangY.QiY. X.QiZ.TsangS. Y. (2019). TRPC3 Regulates the Proliferation and Apoptosis Resistance of Triple Negative Breast Cancer Cells Through the TRPC3/RASA4/MAPK Pathway. Cancers11 (4), 558. 10.3390/cancers11040558

  • CrossRef
  • Google Scholar

• 155

  WasilenkoW. J.PaladA. J.SomersK. D.BlackmoreP. F.KohnE. C.RhimJ. S.et al (1996). Effects of the Calcium Influx Inhibitor Carboxyamido-Triazole on the Proliferation and Invasiveness of Human Prostate Tumor Cell Lines. Int. J. Cancer68 (2), 259–264. 10.1002/(SICI)1097-0215(19961009)68:2<259::AID-IJC20>3.0.CO;2-4

  • CrossRef
  • Google Scholar

• 156

  WatanabeH.TakahashiR.ZhangX.-X.KakizawaH.HayashiH.OhnoR. (1996). Inhibition of Agonist-Induced Ca2+Entry in Endothelial Cells by Myosin Light-Chain Kinase Inhibitor. Biochem. Biophys. Res. Commun.225 (3), 777–784. 10.1006/bbrc.1996.1250

  • CrossRef
  • Google Scholar

• 157

  WeiM.ZhouY.SunA.MaG.HeL.ZhouL.et al (2016). Molecular Mechanisms Underlying Inhibition of STIM1-Orai1-Mediated Ca2+ Entry Induced by 2-Aminoethoxydiphenyl Borate. Pflugers Arch.468 (11–12), 2061–2074. 10.1007/s00424-016-1880-z

  • CrossRef
  • Google Scholar

• 158

  WenL.VoroninaS.JavedM. A.AwaisM.SzatmaryP.LatawiecD.et al (2015). Inhibitors of ORAI1 Prevent Cytosolic Calcium-Associated Injury of Human Pancreatic Acinar Cells and Acute Pancreatitis in 3 Mouse Models. Gastroenterology149 (2), 481–492. 10.1053/j.gastro.2015.04.015

  • CrossRef
  • Google Scholar

• 159

  WilliamsR. T.ManjiS. S. M.ParkerN. J.HancockM. S.Van StekelenburgL.EidJ.-P.et al (2001). Identification and Characterization of the STIM (Stromal Interaction Molecule) Gene Family: Coding for a Novel Class of Transmembrane Proteins. Biochem. J.357 (Pt 3), 673–685. 10.1042/0264-6021:3570673

  • CrossRef
  • Google Scholar

• 160

  WorleyP. F.ZengW.HuangG. N.YuanJ. P.KimJ. Y.LeeM. G.et al (2007). TRPC Channels as STIM1-Regulated Store-Operated Channels. Cell Calcium42 (2), 205–211. 10.1016/j.ceca.2007.03.004

  • CrossRef
  • Google Scholar

• 161

  WuY.PaladA. J.WasilenkoW. J.BlackmoreP. F.PincusW. A.SchechterG. L.et al (1997). Inhibition of Head and Neck Squamous Cell Carcinoma Growth and Invasion by the Calcium Influx Inhibitor Carboxyamido-Triazole. Clin. Cancer Res.3 (11), 1915–1921.

  • Google Scholar

• 162

  WuM. L.ChenW. H.LiuI. H.TsengC. D.WangS. M. (1999). A Novel Effect of Cyclic AMP on Capacitative Ca2+ Entry in Cultured Rat Cerebellar Astrocytes. J. Neurochem.73 (3), 1318–1328. 10.1046/j.1471-4159.1999.0731318.x

  • CrossRef
  • Google Scholar

• 163

  WuY.-L.XieJ.AnS.-W.OliverN.BarrezuetaN. X.LinM.-H.et al (2017). Inhibition of TRPC6 Channels Ameliorates Renal Fibrosis and Contributes to Renal protection by Soluble Klotho. Kidney Int.91 (4), 830–841. 10.1016/j.kint.2016.09.039

  • CrossRef
  • Google Scholar

• 164

  XiaJ.WangH.HuangH.SunL.DongS.HuangN.et al (2016). Elevated Orai1 and STIM1 Expressions Upregulate MACC1 Expression to Promote Tumor Cell Proliferation, Metabolism, Migration, and Invasion in Human Gastric Cancer. Cancer Lett.381 (1), 31–40. 10.1016/j.canlet.2016.07.014

  • CrossRef
  • Google Scholar

• 165

  XieJ.PanH.YaoJ.ZhouY.HanW. (2016). SOCE and Cancer: Recent Progress and New Perspectives. Int. J. Cancer138 (9), 2067–2077. 10.1002/ijc.29840

  • CrossRef
  • Google Scholar

• 166

  XuS.-Z.ZengF.BoulayG.GrimmC.HarteneckC.BeechD. J. (2005). Block of TRPC5 Channels by 2-Aminoethoxydiphenyl Borate: a Differential, Extracellular and Voltage-Dependent Effect. Br. J. Pharmacol.145 (4), 405–414. 10.1038/sj.bjp.0706197

  • CrossRef
  • Google Scholar

• 167

  XuY.ZhangS.NiuH.YeY.HuF.ChenS.et al (2015). STIM1 Accelerates Cell Senescence in a Remodeled Microenvironment But Enhances the Epithelial-to-Mesenchymal Transition in Prostate Cancer. Sci. Rep.5, 11754. 10.1038/srep11754

  • CrossRef
  • Google Scholar

• 168

  XuX.AliS.LiY.YuH.ZhangM.LuJ.et al (2016). 2-Aminoethoxydiphenyl Borate Potentiates CRAC Current by Directly Dilating the Pore of Open Orai1. Sci. Rep.6, 29304. 10.1038/srep29304

  • CrossRef
  • Google Scholar

• 169

  YamashitaM.Navarro-BorellyL.McNallyB. A.PrakriyaM. (2007). Orai1 Mutations Alter Ion Permeation and Ca2+-Dependent Fast Inactivation of CRAC Channels: Evidence for Coupling of Permeation and Gating. J. Gen. Physiol.130 (5), 525–540. 10.1085/jgp.200709872

  • CrossRef
  • Google Scholar

• 170

  YamashitaM.SomasundaramA.PrakriyaM. (2011). Competitive Modulation of Ca2+ Release-Activated Ca2+ Channel Gating by STIM1 and 2-Aminoethyldiphenyl Borate. J. Biol. Chem.286 (11), 9429–9442. 10.1074/jbc.M110.189035

  • CrossRef
  • Google Scholar

• 171

  YangH.MerglerS.SunX.WangZ.LuL.BonannoJ. A.et al (2005). TRPC4 Knockdown Suppresses Epidermal Growth Factor-Induced Store-Operated Channel Activation and Growth in Human Corneal Epithelial Cells. J. Biol. Chem.280 (37), 32230–32237. 10.1074/jbc.M504553200

  • CrossRef
  • Google Scholar

• 172

  YangS.ZhangJ. J.HuangX.-Y. (2009). Orai1 and STIM1 are Critical for Breast Tumor Cell Migration and Metastasis. Cancer Cell15 (2), 124–134. 10.1016/j.ccr.2008.12.019

  • CrossRef
  • Google Scholar

• 173

  YangN.TangY.WangF.ZhangH.XuD.ShenY.et al (2013). Blockade of Store-Operated Ca2+ Entry Inhibits Hepatocarcinoma Cell Migration and Invasion by Regulating Focal Adhesion Turnover. Cancer Lett.330 (2), 163–169. 10.1016/j.canlet.2012.11.040

  • CrossRef
  • Google Scholar

• 174

  YeJ.HuangJ.HeQ.ZhaoW.ZhouX.ZhangZ.et al (2018). Blockage of Store-Operated Ca2+ Entry Antagonizes Epstein-Barr Virus-Promoted Angiogenesis by Inhibiting Ca2+ Signaling-Regulated VEGF Production in Nasopharyngeal Carcinoma. Cancer Manag. Res.10, 1115–1124. 10.2147/cmar.S159441

  • CrossRef
  • Google Scholar

• 175

  YoshidaJ.IwabuchiK.MatsuiT.IshibashiT.MasuokaT.NishioM. (2012). Knockdown of Stromal Interaction Molecule 1 (STIM1) Suppresses Store-Operated Calcium Entry, Cell Proliferation and Tumorigenicity in Human Epidermoid Carcinoma A431 Cells. Biochem. Pharmacol.84 (12), 1592–1603. 10.1016/j.bcp.2012.09.021

  • CrossRef
  • Google Scholar

• 176

  YuanJ. P.ZengW.DorwartM. R.ChoiY.-J.WorleyP. F.MuallemS. (2009). SOAR and the Polybasic STIM1 Domains Gate and Regulate Orai Channels. Nat. Cell Biol.11 (3), 337–343. 10.1038/ncb1842

  • CrossRef
  • Google Scholar

• 177

  ZagranichnayaT. K.WuX.VillerealM. L. (2005). Endogenous TRPC1, TRPC3, and TRPC7 Proteins Combine to Form Native Store-Operated Channels in HEK-293 Cells. J. Biol. Chem.280 (33), 29559–29569. 10.1074/jbc.M505842200

  • CrossRef
  • Google Scholar

• 178

  ZakharovS. I.SmaniT.DobrydnevaY.MonjeF.FichandlerC.BlackmoreP. F.et al (2004). Diethylstilbestrol is a Potent Inhibitor of Store-Operated Channels and Capacitative Ca(2+) Influx. Mol. Pharmacol.66 (3), 702–707. 10.1124/mol.66.310.1124/mol.66.3

  • CrossRef
  • Google Scholar

• 179

  ZangJ.ZuoD.ZuoD.L. ShogrenK.T. GustafsonC.ZhouZ.et al (2019). STIM1 Expression is Associated With Osteosarcoma Cell Survival. Chin. J. Cancer Res.31 (1), 203–211. 10.21147/j.issn.1000-9604.2019.01.15

  • CrossRef
  • Google Scholar

• 180

  ZengB.YuanC.YangX.L. AtkinS.XuS.-Z. (2013). TRPC Channels and Their Splice Variants are Essential for Promoting Human Ovarian Cancer Cell Proliferation and Tumorigenesis. Curr. Cancer Drug Targets13 (1), 103–116. 10.2174/156800913804486629

  • CrossRef
  • Google Scholar

• 181

  ZhangX.-F.IwamuroY.EnokiT.OkazawaM.LeeK.KomuroT.et al (1999). Pharmacological Characterization of Ca2+ Entry Channels in Endothelin-1-Induced Contraction of Rat Aorta Using LOE 908 and SK&F 96365. Br. J. Pharmacol.127 (6), 1388–1398. 10.1038/sj.bjp.0702661

  • CrossRef
  • Google Scholar

• 182

  ZhangJ.WeiJ.KanadaM.YanL.ZhangZ.WatanabeH.et al (2013). Inhibition of Store-Operated Ca2+ Entry Suppresses EGF-Induced Migration and Eliminates Extravasation From Vasculature in Nasopharyngeal Carcinoma Cell. Cancer Lett.336 (2), 390–397. 10.1016/j.canlet.2013.03.026

  • CrossRef
  • Google Scholar

• 183

  ZhangJ.HeQ.YeJ.ZhangZ.LiY.WeiJ.et al (2015). SKF95365 Induces Apoptosis and Cell-Cycle Arrest by Disturbing Oncogenic Ca2+ Signaling in Nasopharyngeal Carcinoma Cells. Onco. Targets Ther.8, 3123–3133. 10.2147/ott.S92005

  • CrossRef
  • Google Scholar

• 184

  ZhouY.MeranerP.KwonH. T.MachnesD.Oh-horaM.ZimmerJ.et al (2010). STIM1 Gates the Store-Operated Calcium Channel ORAI1 In Vitro. Nat. Struct. Mol. Biol.17 (1), 112–116. 10.1038/nsmb.1724

  • CrossRef
  • Google Scholar

• 185

  ZittC.StraussB.SchwarzE. C.SpaethN.RastG.HatzelmannA.et al (2004). Potent Inhibition of Ca2+ Release-Activated Ca2+ Channels and T-Lymphocyte Activation by the Pyrazole Derivative BTP2. J. Biol. Chem.279 (13), 12427–12437. 10.1074/jbc.M309297200

  • CrossRef
  • Google Scholar

• 186

  ZubcevicL.HerzikM. A.Jr.WuM.BorschelW. F.HirschiM.SongA. S.et al (2018). Conformational Ensemble of the Human TRPV3 Ion Channel. Nat. Commun.9 (1), 4773. 10.1038/s41467-018-07117-w

  • CrossRef
  • Google Scholar