Even Cancer Cells Watch Their Cholesterol!

Abstract

Deregulated cell proliferation is an established feature of cancer, and altered tumor metabolism has witnessed renewed interest over the past decade, including the study of how cancer cells rewire metabolic pathways to renew energy sources and "building blocks" that sustain cell division. Microenvironmental oxygen, glucose, and glutamine are regarded as principal nutrients fueling tumor growth. However, hostile tumor microenvironments render O₂/nutrient supplies chronically insufficient for increased proliferation rates, forcing cancer cells to develop strategies for opportunistic modes of nutrient acquisition. Recent work shows that cancer cells overcome this nutrient scarcity by scavenging other substrates, such as proteins and lipids, or utilizing adaptive metabolic pathways. As such, reprogramming lipid metabolism plays important roles in providing energy, macromolecules for membrane synthesis, and lipid-mediated signaling during cancer progression. In this review, we highlight more recently appreciated roles for lipids, particularly cholesterol and its derivatives, in cancer cell metabolism within intrinsically harsh tumor microenvironments.

Keywords: bile acids; cancer; cholesterol; lipids; metabolism; oxysterols.

Figure 1.. Overview of Major Metabolic Pathways Altered in Cancer

This figure highlights up- (red) and down-regulated (blue) metabolic pathways in cancer cells. Glucose and glutamine are common precursors of fatty acids and cholesterol, through increased glycolysis and/or glutaminolysis. (*) of note, β-oxidation processes usually occur inside the mitochondria. ADP: adenosine diphosphate, ATP: adenosine triphosphate, CD36: “cluster of differentiation” 36, CPT-1: carnitine palmitoyltransferase 1, GLUT-1: glucose transporter 1, LDLR: low density lipoprotein receptor, MCT-1: monocarboxylate transporter 1, MPC: mitochondrial pyruvate carrier, SCARB-1: scavenger receptor B1, SLC1A5: solute carrier family 1 (neutral amino acid transporter) member 5.

Figure 2.. Cholesterol De Novo Synthesis and Derivative Molecules

This represents a simplified cholesterol biosynthetic pathway, also called the “mevalonate” pathway, and major cholesterol derivatives (oxysterols, bile acids, steroid hormones and vitamins). High cholesterol/oxysterol content inhibits (−) de novo synthesis through SREBPs inactivation and activates LXRs, which stimulates (+) bile acid production and inhibits (−) cholesterol uptake. ADP: adenosine diphosphate, ATP: adenosine triphosphate, LXR: liver X receptor, NADP/NADPH: nicotinamide adenine dinucleotide phosphate, SREBPs: sterol regulatory element-binding proteins.

Figure 3.. Potential Roles of Cellular Cholesterol

Cancer cells rely on de novo synthesis for their cholesterol and cholesterol ester (free cholesterol bound to fatty acids) pools, but can also take up exogenous free cholesterol and cholesterol esters, through HDL (CE enriched and TG low), LDL (CE and TG enriched) and VLDL (CE low and TG enriched) lipoproteins, to meet their cholesterol requirements. Cholesterol can then be used for membrane synthesis, lipid raft signaling or steroid synthesis. When in excess (and to avoid free cholesterol toxicity), cholesterol is locally stored within lipid droplets in a cholesterol ester form. It can also be directly exported or converted into bile acid first and then excreted. Cholesterol-bound fatty acids are broken down to produce energy through mitochondrial β-oxidation. (*) of note, β-oxidation process usually occurs inside the mitochondria. ABCA-1: ATP-binding cassette subfamily A member 1, ABCGs: ATP-binding cassette subfamily G, CE: cholesterol ester, HDL: high density lipoprotein, LDL: low density lipoprotein, LDLR: low density lipoprotein receptor, ROS: reactive oxygen species, SCARB-1: scavenger receptor B1, TG: triglyceride, VLDL: very low-density lipoprotein, VLDLR: very low-density lipoprotein receptor.