Abstract
Cholesterol is a lipid molecule that plays an essential role in a number of biological processes, both physiological and pathological. It is an essential structural constituent of cell membranes, and it is fundamental for biosynthesis, integrity, and functions of biological membranes, including membrane trafficking and signaling. Moreover, cholesterol is the major lipid component of lipid rafts, a sort of lipid-based structures that regulate the assembly and functioning of numerous cell signaling pathways, including those related to cancer, such as tumor cell growth, adhesion, migration, invasion, and apoptosis. Considering the importance of cholesterol metabolism, its homeostasis is strictly regulated at every stage: import, synthesis, export, metabolism, and storage. The alterations of this homeostatic balance are known to be associated with cardiovascular diseases and atherosclerosis, but mounting evidence also connects these behaviors to increased cancer risks. Although there is conflicting evidence on the role of cholesterol in cancer development, most of the studies consistently suggest that a dysregulation of cholesterol homeostasis could lead to cancer development. This review aims to discuss the current understanding of cholesterol homeostasis in normal and cancerous cells, summarizing key findings from recent preclinical and clinical studies that have investigated the role of major players in cholesterol regulation and the organization of lipid rafts, which could represent promising therapeutic targets.
Highlights
Cholesterol is a primary lipid molecule that plays an essential role in a number of biological processes, both at physiological and pathological level (Maxfield and Tabas, 2005).Abbreviations: ABCA1, ATP-binding cassette subfamily A member 1; ABC subfamily G member 1 (ABCG1), ATP-binding cassette subfamily G member 1; ACAT1, acyl-CoA:cholesteryl acyltransferase 1; AMPK, 5 adenosine monophosphate-activated protein kinase; AMPK, AMP-activated protein kinase; ApoA-I, lipid-poor apolipoprotein A-I; cholesteryl esters (CEs), cholesteryl ester; ER, endoplasmic reticulum; FPP, farnesyl pyrophosphate; FPP, farnesyl pyrophosphate; Farnesyl transferase (FTase), farnesyl transferase; GGPP, geranylgeranyl pyrophosphate
This review aims to discuss the current knowledge of cholesterol homeostasis, critically analyzing the most recent preclinical and clinical studies investigating the role of the principal players of the cholesterol biosynthetic pathway, and of the cholesterol-based membrane structure’s lipid rafts in the field of cancer
Several findings reported the localization within lipid rafts of the highly expressed cell surface adhesion receptor CD44, whose lipid raft localization was related to invasion and metastatic processes of cancer cells (Murai, 2015; Mollinedo and Gajate, 2020)
Summary
Cholesterol is a primary lipid molecule that plays an essential role in a number of biological processes, both at physiological and pathological level (Maxfield and Tabas, 2005). GGTase, geranylgeranyl transferases; HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-methyl-glutaryl CoA; HMGR, HMG reductase; IGF, insulin-like growth factor; INSIGs, insulin-induced gene; LDL, low-density lipoprotein; LDLR, LDL receptor; LXR, liver X receptor; MβCD, methyl-β-cyclodextrin; miRNA, microRNA; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1; NPC1L1, Niemann–Pick type C1-like 1; PI3K, phosphatidylinositol 3kinase; SCAP, SREBP cleavage activating protein; sGTPase, small GTP-binding protein; SOAT, sterol-o-acyltransferase; SQL, squalene; SQLE, squalene epoxidase; SRE, sterol regulatory element; SREBP2, sterol regulatory element-binding protein 2; VLDL, very-low-density lipoprotein
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