The Pivotal Role of the Dysregulation of Cholesterol Homeostasis in Cancer: Implications for Therapeutic Targets

Abstract

Cholesterol plays an important role in cellular homeostasis by maintaining the rigidity of cell membranes, providing a medium for signaling transduction, and being converted into other vital macromolecules, such as sterol hormones and bile acids. Epidemiological studies have shown the correlation between cholesterol content and cancer incidence worldwide. Accumulating evidence has shown the emerging roles of the dysregulation of cholesterol metabolism in cancer development. More specifically, recent reports have shown the distinct role of cholesterol in the suppression of immune cells, regulation of cell survival, and modulation of cancer stem cells in cancer. Here, we provide a comprehensive review of the epidemiological analysis, functional roles, and mechanistic action of cholesterol homeostasis in regard to its contribution to cancer development. Based on the existing data, cholesterol homeostasis is identified to be a new key player in cancer pathogenesis. Lastly, we also discuss the therapeutic implications of natural compounds and cholesterol-lowering drugs in cancer prevention and treatment. In conclusion, intervention in cholesterol metabolism may offer a new therapeutic avenue for cancer treatment.

Keywords: cancer; cancer stem cells; cholesterol esters; cholesterol homeostasis; cholesterol-lowering drugs; immunotherapy; lipoproteins; oxysterols; statins.

Figure 1

Cholesterol metabolism and key oncogenic pathways related to cancer development. (a) Cholesterol de novo biosynthesis. Starting from three molecules of acetyl-coenzyme A (CoA), cholesterol is synthesized in more than 20 enzymatic steps, whereas 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and squalene epoxidase (SQLE) act as rate-limiting enzymes. (b) Systematic diagram showing the cholesterol metabolism in relation to key oncogenic molecular pathways. Sterol-regulatory element binding protein 2 (SREBP2) regulates the transcriptional activity of cholesterol biosynthesis genes, low density lipoprotein receptor (LDLR)-mediated cholesterol influx, and Nod-like receptor protein 3 (NLRP3) inflammasome-associated inflammation. Embedded in SREBP2 gene, microRNA (miRNA)-33 can positively regulate SREBP2 expression. The over-activated cholesterol biosynthesis contributes to uncontrolled cell growth. Overexpressed proprotein-convertase-subtilisin-kexin type-9 (PCSK9) facilities the lysosomal degradation of LDLR, induces hypercholesterolemia, and eventually leads to the development of hepatocellular carcinoma. Excess cholesterol is exported via ATP-binding cassette (ABC) subfamily A member 1 (ABCA1) under liver X receptor (LXR) activation. However, in cancercells, ABCA1 is prohibited by the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin complex 1 (mTORC1) pathway. The overall retention of intracellular cholesterol facilitates acyl-CoA:cholesteryl acyltransferase 1 (ACAT1), converting cholesterol into cholesteryl esters, leading to the development of different types of cancer. ABCA1 can also be inhibited by miRNA-27 and miRNA-183. TP53-mediated SREBP2 activation increases the production of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) in the mevalonate pathway, resulting in prenylation of small Ras family GTPases and their downstream effectors. An increased SQLE level under high nuclear SREBP2 (nSREBP2) induction inhibits phosphatase and tensin homolog (PTEN) activity and sequentially allows the PI3K/Akt/mTORC1 signaling cascade. Lastly, cholesterol or its oxidative derivatives activate Smoothened receptor (SMO) in the sonic hedgehog (SHH) pathway. The overall alterations in these pathways increase the proliferation rate and the migration and invasion capacities, allow cell survival, and induce tumor formation.