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Editorial ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Endocrinol. | doi: 10.3389/fendo.2019.00732

Editorial: "Cholesterol and Oxysterol as Signal Molecules in Human Pathophysiology and Cancer: Implication for New Therapeutic Strategies"

  • 1University of Calabria, Italy
  • 2University of Houston, United States
  • 3Department of Pharmacy and Health and Nutrition Science, University of Calabria, Italy

This collection is focused on the role of Chol and/or oxysterols as signaling molecules whose alteration can determine the onset or progression of pathologies. Consequently, modulation of sterol homeostasis represent a promising therapeutic strategy. Yamamuchi and Rogers in this collection reviewed the connection between sterol metabolism and atherosclerosis as well as cancers. Their paper focuses on several drugs including those currently used in clinic (i.e.statins to block cholesterol synthesis and enhance LDL uptake) and those targeting sterol metabolism in preclinical and clinical studies (i.e. drugs targeting SREBPs and SREBP regulators, LXR, ABC transporters, ACAT, and sterol hydroxylases). Cholesterol-free reconstituted or synthetic HDL (sHDL) represent a new reasonable strategy for delivering chemotherapeutic drugs to cancer cells. HDL receptor (Scavenger receptor type B-I; SR-BI), is highly expressed in endocrine cancers, notably due to the high demand for cholesterol by cancer cells. Binding sHDL loaded with a chemotherapic will deplete Chol while assuring specificity for cancer cells. This attractive approach is reviewed by Morin et al. suggesting the application of sHDLs as endocrine cancer therapeutics.Patients suffering from hyperlipidemia or metabolic syndrome clearly evidence a link between male reproductive function and cholesterol homeostasis. Sedes et al. in this collection highlighted molecular mechanisms involving nuclear receptors LXRs and FXRα and their sterol ligands important for testicular function. Drugs targeting these nuclear receptors could be used in the clinic either to treat male infertility or as new approach for male contraception.Another interesting aspect is evidenced by Oguro reviewing in this collection recent advances in our understanding of the roles of Chol and its metabolites as signaling molecules in the regulation of hematopoiesis and hematologic malignancies. In particular, cholesterol metabolism to steroids and oxysterols promotes hematologic cancers, and statins that inhibit de novo cholesterol synthesis have cytotoxic effects in malignant hematopoietic cells.The therapeutic potential of statins for the treatment of solid cancer has been reviewed in this collection by Chimento et al.. Statins prevent cancer growth and metastasis by interfering with cholesterol activities which include signal molecule on membrane rafts, substrate for steroids, oxysterols and Vitamin D3 synthesis, ligand for estrogen-related receptor alpha (ERRα). This last aspect that proposes cholesterol as an endogenous ERRα agonist has been reviewed in deep by Casaburi et al. In several cancer cells, the expression and the activity of ERRα, together with its cofactors (PGC-1 α/β), is further influenced by oncogenic signals and can thus be re-directed to induce metabolic programs favoring tumor growth and progression (7). Based on these considerations, the use of therapeutic strategies aimed to reduce cholesterol levels, such as statins or drugs targeting the SREBP metabolic pathways, could be a promising option to counteract metabolic rewiring in cancer cells where ERRα plays a pivotal role. Another relevant signal molecoles binding nuclear receptors and involved in cancer progression is the oxysterol 27-hydroxycholesterol (27HC). 27HC is an abundant cholesterol metabolite in human circulation and promotes breast cancer cell proliferation (8,9). Hiramitsu et al. in this collection clearly describe how this oxysterol promotes also lung cancer cell proliferation through Estrogen Receptor β/PI3K-Akt signaling. Thus, lowering 27HC levels may lead to a novel approach for the treatment of lung cancer. Oxysterols are also involved in pathology of three major gastrointestinal cancer (hepatocellular carcinoma, pancreatic, and colon cancer). Kovac et al. in this collection suggest an interesting theory on the circadian clock effects on gastrointestinal carcinogenesis by regulating the lipid metabolism and beyond. With this in mind, classical therapies (statins) to modulate cholesterol in gastrointestinal cancers, must be administred at a proper time and for a proper duration (chronotherapy) for successful therapies.In conclusion, from this collection emerges that regulation of sterol homeostasis is a complex network of transcription factors, protein modifiers, sterol transporters/carriers, sterol sensors disregulated in various pathological settings such as atheroscerosis, cancers and neurodegenerative diseases. In this context Chol and oxysterol as signal molecules are an appealing target to counteract these pathologies. New strategies aimed to modulate their levels and actions in different tissues are worth to be developed.

Keywords: Cholesterol (chol), oxysterol, Cancer, Signal molecule pathways, Nuclear receptor (NR)

Received: 17 Sep 2019; Accepted: 10 Oct 2019.

Copyright: © 2019 Sirianni, Umetani and Pezzi. 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) and the copyright owner(s) 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: Prof. Vincenzo Pezzi, University of Calabria, Department of Pharmacy and Health and Nutrition Science, Arcavacata, 87036, Italy, v.pezzi@unical.it