title: Could drugs inhibiting the mevalonate pathway also target cancer stem cells?
abstract: Understanding the connection between metabolic pathways and cancer is very important for the development of new therapeutic approaches based on regulatory enzymes in pathways associated with tumorigenesis. The mevalonate cascade and its rate-liming enzyme HMG CoA-reductase has recently drawn the attention of cancer researchers because strong evidences arising mostly from epidemiologic studies, show that it could promote transformation. Hence, these studies pinpoint HMG CoA-reductase as a candidate proto-oncogene. Several recent epidemiological studies, in different populations, have proven that statins are beneficial for the treatment-outcome of various cancers, and may improve common cancer therapy strategies involving alkylating agents, and antimetabolites. Cancer stem cells/cancer initiating cells (CSC) are key to cancer progression and metastasis. Therefore, in the current review we address the different effects of statins on cancer stem cells. The mevalonate cascade is among the most pleiotropic, and highly interconnected signaling pathways. Through G-protein-coupled receptors (GRCP), it integrates extra-, and intracellular signals. The mevalonate pathway is implicated in cell stemness, cell proliferation, and organ size regulation through the Hippo pathway (e.g. Yap/Taz signaling axis). This pathway is a prime preventive target through the administration of statins for the prophylaxis of obesity-related cardiovascular diseases. Its prominent role in regulation of cell growth and stemness also invokes its role in cancer development and progression. The mevalonate pathway affects cancer metastasis in several ways by: (i) affecting epithelial-to-mesenchymal transition (EMT), (ii) affecting remodeling of the cytoskeleton as well as cell motility, (iii) affecting cell polarity (non-canonical Wnt/planar pathway), and (iv) modulation of mesenchymal-to-epithelial transition (MET). Herein we provide an overview of the mevalonate signaling network. We then briefly highlight diverse functions of various elements of this mevalonate pathway. We further discuss in detail the role of elements of the mevalonate cascade in stemness, carcinogenesis, cancer progression, metastasis and maintenance of cancer stem cells.
authors.affiliation: Department of Human Anatomy, School of Medicine in Katowice, Medical University of Silesia, 18 Medyków Street, 40-752 Katowice, Poland.
authors.forename: Wirginia
authors.initials: W
authors.lastname: Likus
authors.affiliation: Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, 18 Medyków Street, 40-752 Katowice, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Siemianowicz
authors.affiliation: Interdisciplinary Nanoscience Center (iNANO), Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Konrad
authors.initials: K
authors.lastname: Bieńk
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Pakuła
authors.affiliation: Indian Institute of Science Education and Research (IISER TVM), Thiruvananthapuram, Kerala, India.
authors.forename: Himani
authors.initials: H
authors.lastname: Pathak
authors.affiliation: Department of Clinical & Experimental Medicine (IKE), Linköping University, Linköping, Sweden.
authors.forename: Chhanda
authors.initials: C
authors.lastname: Dutta
authors.affiliation: Department of Physics, Chemistry and Biology (IFM), Division of Biotechnology, Linköping University, Linköping, Sweden.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Shahla
authors.initials: S
authors.lastname: Shojaei
authors.affiliation: The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Yehuda G
authors.initials: YG
authors.lastname: Assaraf
authors.affiliation: Department of Human Anatomy and Cell Science, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Health Research Policy Center, Shiraz University of Medical Science, Shiraz, Iran.
authors.forename: Saeid
authors.initials: S
authors.lastname: Ghavami
authors.affiliation: Institute of Automatic Control, Silesian University of Technology, Gliwice, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Cieślar-Pobuda
authors.affiliation: LinkoCare Life Sciences AB, 583 30 Linköping, Sweden; ENT Department, School of Medicine in Katowice, Medical University of Silesia, 20-24 Francuska Street, 40-027 Katowice, Poland. Electronic address: mjelos@gmail.com.
authors.forename: Marek J
authors.initials: MJ
authors.lastname: Łos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018450:Disease Progression; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D000090063:Proto-Oncogene Mas
chemical_list: D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid
keywords: Cancer stem-like cells; Mevalonate cascade; Ras; Rho; Statins; Stemness; Yap