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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1397116

Natural compound Alternol actives multiple endoplasmic reticulum stressresponding pathways contributing to cell death

Provisionally accepted
WANG LIU WANG LIU 1Chenchen He Chenchen He 2Changlin Li Changlin Li 3Shazhou Ye Shazhou Ye 4Jiang Zhao Jiang Zhao 5Cunle Zhu Cunle Zhu 5Xiangwei Wang Xiangwei Wang 5Qi Ma Qi Ma 4Benyi Li Benyi Li 1*
  • 1 University of Kansas Medical Center, Kansas City, Kansas, United States
  • 2 Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
  • 3 Tianjin Medical University, Tianjin, Tianjin Municipality, China
  • 4 Ningbo University, Ningbo, Zhejiang Province, China
  • 5 Guangdong Medical University, Zhanjiang, Guangdong, China

The final, formatted version of the article will be published soon.

    Alternol is a small molecule isolated from the fermentation of a mutant fungus obtained from Taxus brevifolia bark. Our previous studies showed that Alternol treatment induced reactive oxygen species (ROS)-dependent immunogenic cell death. In this study, a comprehensive investigation was conducted to explore the mechanisms involved in Alternol-induced immunogenic cell death. Our results showed that Alternol interacted with multiple cellular chaperone proteins and increased their expression levels, including endoplasmic reticulum (ER) chaperone hypoxia up-regulated 1 (HYOU1) and heat shock protein 90 alpha family class B member 1 (HSP90AB1), as well as cytosolic chaperone heat shock protein family A member 8 (HSPA8). These data indicated a potential mechanistic cause of unfolded protein response (UPR) after Alternol treatment. Further investigation revealed that Alternol treatment triggered ROS-dependent ER stress responses via protein kinase R-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and the double-stranded RNA-dependent protein kinase (PKR) but not activating transcription factor 6 (ATF6) cascades, leading to ATF-3/ATF-4 activation, C/EBP-homologous protein (CHOP) overexpression, and X-box binding protein XBP1 splicing induction. In addition, inhibition of these ER stress cascades blunted Alternol-induced extracellular adenosine triphosphate (ATP) release, one of the classical hallmarks of immunogenic cell death. Taken together, our data demonstrate that Alternol treatment triggered multiple ER stress cascades, potentially leading to immunogenic cell death.

    Keywords: er stress, pERK, IRE1 prostate cancer, Heat-Shock Proteins, ATP release

    Received: 06 Mar 2024; Accepted: 02 May 2024.

    Copyright: © 2024 LIU, He, Li, Ye, Zhao, Zhu, Wang, Ma and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Benyi Li, University of Kansas Medical Center, Kansas City, KS 66160, Kansas, United States

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