Dysregulation of cholesterol homeostasis in cancer pathogenesis

Abstract

Cholesterol is a unique lipid for all mammalian cells, with important functions in membrane biogenesis and maintenance of proper membrane integrity and fluidity. Therefore, it plays an important role in cellular homeostasis. Dysregulation of cholesterol homeostasis is associated with various diseases in humans, including cardiovascular diseases, inflammatory diseases, neurodegenerative disorders, and cancers. In the tumor microenvironment, intrinsic and extrinsic cellular factors reprogram cholesterol metabolism and consequently promote tumorigenesis. Here, we summarize the current knowledge on molecular mechanisms and functional roles of cholesterol homeostasis and its dysregulation in regard to cancer pathogenesis. We also discuss the interplay of cholesterol metabolism and the ATP-binding cassette (ABC) proteins, highly conserved cellular transmembrane lipid transporters. An emerging role of lipid ABC transporters as potential prognostic tools for cancer progression and invasiveness is emphasized. Targeting both cholesterol metabolism and proteins associated with membrane cholesterol holds promise as a novel therapeutic strategy for cancer treatment.

Keywords: ATP-binding cassette transporters; Cancer; Cancer progression; Cholesterol metabolism; Membrane cholesterol; Tumor microenvironment.

Fig. 1

Landmark discoveries in cholesterol biology. The timeline of selected cholesterol-related discoveries, including selected discoveries in the context of cancer biology. Nobel Prize discoveries were indicated in blue boxes (reviewed by: [–14]). Created in https://BioRender.com

Fig. 2

Regulation of cholesterol homeostasis in the body. Endogenous synthesis in the liver and dietary intake are two main sources of cholesterol in the body. Cholesterol synthesized de novo in hepatocytes is converted into cholesterol esters and exported via the very-low-density lipoprotein (VLDL) particles or loaded as free cholesterol into apolipoprotein A1 (ApoA1) to form high-density lipoprotein (HDL) molecules, a process mediated by ABCA1 and ABCG1 proteins. In the plasma, VLDL is converted into intermediate-density lipoprotein (IDL) and next low-density lipoprotein (LDL), which is the main carrier of the endogenous cholesterol to peripheral tissues. Cholesterol can also be absorbed from the diet, incorporated into the particles called chylomicrons and transported from the intestine to the circulation. The LDL molecules and chylomicron remnants are taken up by the low-density lipoprotein receptors (LDLR) in hepatocytes, peripheral tissues and macrophages, endocytosed and hydrolyzed to release free cholesterol. ABCA1 and ABCG1 mediate the efflux of free cholesterol from macrophages and peripheral tissues to ApoA1, which then forms HDL. HDL is subsequently transported back to the liver (a process known as reverse cholesterol transport, RTC) and uptaken by Scavenger receptor B1 (SR-B1), which is expressed on hepatocytes. NCEH – neutral cholesteryl ester hydrolase; SOAT – sterol-O-acyltransferase. Created in https://BioRender.com

Fig. 3

Cholesterol homeostasis in a typical mammalian cell. (1) Cholesterol is synthesized endogenously from acetyl-CoA in the ER. (2) LDL-derived cholesterol is delivered through the endosomal trafficking system, where LDL binds to the low-density lipoprotein receptors (LDLR) on the cell membrane and is internalized via endocytosis. In lysosomes, cholesterol is released from LDL and transported out of the vesicle as free cholesterol (FC). High levels of intracellular cholesterol lead to the suppression of SREBP2 transcription factor, resulting in decreased synthesis and uptake of cholesterol into the cell. (3) Excess cholesterol is converted into cholesterol ester (CE) by the enzyme sterol-O-acyltransferase 1 (SOAT1) and stored in the form of lipid droplets. (4) Some fraction of this cholesterol can be converted back to unesterified cholesterol via the enzyme-neutral cholesteryl ester hydrolase (NCEH). This free cholesterol is then either utilized by the cell or removed, and any excess is converted into oxysterols. (5) Oxysterols activate the liver X receptor (LXR)-retinoid X receptor (RXR) pathway, leading to increased expression levels of ABCA1 and ABCG1 proteins, which promote cholesterol efflux. HMGCR – 3-hydroxy-methylglutaryl-CoA reductase; FDFT1 – farnesyl-diphosphate farnesyltransferase 1; SQLE – squalene epoxidase. Created in https://BioRender.com

Fig. 4

The factors that affect cholesterol metabolism in cancer. Cholesterol metabolism may be affected by many factors, with the major listed here. *While increased cholesterol biosynthesis is more commonly observed in cancer cells due to their high demands for cholesterol to support rapid proliferation, membrane synthesis, and signaling, cholesterol biosynthesis may be decreased in specific contexts or depending on the cancer type. Created in https://BioRender.com

Fig. 5

The role of ABCA1 as a tumor suppressor or tumor promoter in various cancer types. Description in text. Created in https://BioRender.com

Fig. 6

Illustration of populations of tumor-associated macrophages (TAMs) and their role in cancer. There are two phenotypes of TAMs distinguished, pro-inflammatory M1 phenotype, which has an anti-tumoral effect and anti-inflammatory M2 phenotype, which has a pro-tumoral effect. A detailed description of how cholesterol metabolism can regulate the recruitment and activity of TAMs in the text. Created in https://BioRender.com

Fig. 7

Schematic representation of the immunosuppressive function of extracellular cholesterol in the tumor microenvironment (TME). The accumulation of cholesterol in the TME can drive an exhaustion phenotype in CD8 + T-cells, manifested by increased expression of checkpoint inhibitors and decreased secretion of anti-tumor cytokines and proteases [170]. High cholesterol levels in the TME also induce ABCA1 expression in tumor-infiltrating monocytes/macrophages, leading to cholesterol efflux and a shift in macrophages toward an immunosuppressive, anti-inflammatory phenotype characterized by elevated expression of PD-L1 and CD206, as well as changes in the secretion of pro- and anti-inflammatory cytokines [171]. Hypothetically, one source of cholesterol accumulation in the TME may be increased expression of cholesterol efflux transporters such as ABCA1 in tumor cells, as described in several cancer types. Created in https://BioRender.com