Role of Cholesterol and Lipid Rafts in Cancer Signaling: A Promising Therapeutic Opportunity?

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.

Lipid biomarkers and Cancer risk - a population-based prospective cohort study in Taiwan

“…In this study, the association between the decline in blood lipid levels and cancer risk did not change substantially after exclusion of lipid-lowering agent users. The mainstay of these agents, like statin, is believed to inhibit key enzymes in the cholesterol synthesis pathway and may disrupt oncogenesis [ 30 ]. Ambiguous results were obtained with respect to the relationship between the use of lipid-lowering agents and cancer risk.…”

“…Furthermore, prolonged depletion of plasma cholesterol may contribute to tumorigenesis by promoting the activation of nuclear factor-κB [ 41 ]. It could also disrupt the homeostatic balance of lipid raft and dysregulate tumor cell growth [ 30 ]. Finally, the elimination of cholesterol by altered gut microbiota may also facilitate cancer development [ 30 ].…”

Primary cilia and lipid raft dynamics

“…Lipid raft-mediated Akt signalling is over-activated in various types of cancer, including prostate cancer and melanoma royalsocietypublishing.org/journal/rsob Open Biol. 11: 210130 [26,[70][71][72][73]. Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) inhibits Akt activity through dephosphorylation of PIP3 to PIP2 [74].…”

“…Activation of SREBP1 also stimulates PI3K-Akt signalling [84,86]. Various therapeutic approaches for cancer have been developed that target PI3K, PTEN, Akt, PP2A, or the organization of these molecules in lipid rafts [23,71,73,[87][88][89][90][91][92][93]. Interestingly, primary cilia are often lost in prostate cancers and melanoma [94][95][96][97][98] (figure 2).…”

“…Strategies for improving the efficacy and safety of these therapeutic drugs have been actively developed [109][110][111]. Statins can also be classified as anti-cancer agents that inhibit lipid raft-mediated Akt signalling [71,73,103,104].…”