Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy

Abstract

Cholesterol is a ubiquitous sterol with many biological functions, which are crucial for proper cellular signaling and physiology. Indeed, cholesterol is essential in maintaining membrane physical properties, while its metabolism is involved in bile acid production and steroid hormone biosynthesis. Additionally, isoprenoids metabolites of the mevalonate pathway support protein-prenylation and dolichol, ubiquinone and the heme a biosynthesis. Cancer cells rely on cholesterol to satisfy their increased nutrient demands and to support their uncontrolled growth, thus promoting tumor development and progression. Indeed, transformed cells reprogram cholesterol metabolism either by increasing its uptake and de novo biosynthesis, or deregulating the efflux. Alternatively, tumor can efficiently accumulate cholesterol into lipid droplets and deeply modify the activity of key cholesterol homeostasis regulators. In light of these considerations, altered pathways of cholesterol metabolism might represent intriguing pharmacological targets for the development of exploitable strategies in the context of cancer therapy. Thus, this work aims to discuss the emerging evidence of in vitro and in vivo studies, as well as clinical trials, on the role of cholesterol pathways in the treatment of cancer, starting from already available cholesterol-lowering drugs (statins or fibrates), and moving towards novel potential pharmacological inhibitors or selective target modulators.

Keywords: cancer; cancer therapy; cholesterol; metabolic reprogramming; metabolic targeting agents; pharmacological modulation; pharmacological targeting.

Figure 1

Schematic representation of cholesterol biosynthesis. In the first step of cholesterol biosynthesis, three molecules of acetyl-CoA condense to form HMG-CoA, which is then reduced to mevalonate by the first step-limiting enzyme HMG-CoA reductase (HMGCR). Subsequent reactions allow the conversion of mevalonate into FPP, an isoprenoid that gives rise to squalene in a reaction catalyzed by squalene synthase (SQS). Squalene is then converted by the second rate-limiting enzyme squalene epoxidase (SQLE) into its epoxidic form, which is eventually cyclized to lanosterol by the enzyme lanosterol synthase. Further oxygen-based reactions lead to the formation of cholesterol. Red: rate-limiting enzymes. HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; IPP, Isopentyl pyrophosphate; DMAPP, Dimethylallyl pyrophosphate; FPP, Farnesyl pyrophosphate.

Figure 2

Schematic representation of the main alterations in cholesterol metabolism pathway in tumors. Cancer cells are highly proliferative and therefore strongly dependent on cholesterol to sustain the high demand of substrates for membrane biosynthesis. Cancer cells increase their cholesterol demand by enhancing de novo biosynthesis (or exogenous uptake). Increased/overexpressed enzymes in cholesterol biosynthesis pathway are indicated with (↑). HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; SQS, Squalene synthase; SQLE, Squalene epoxidase; ACAT1, Acetyl-CoA Acetyltransferase 1.

Figure 3

(A) Cholesterol metabolism. De novo cholesterol biosynthesis mainly relies on the activity of four key enzymes. HMGCR catalyzes the formation of mevalonate. Mevalonate is essential for farnesyl pyrophosphate biosynthesis, which is in turn exploited by SQS for squalene production. SQL converts squalene into its epoxydic form, which is eventually cyclized to lanosterol by OSC. Lastly, lanosterol is converted to cholesterol. HDL particles collect extrahepatic cholesterol and allow its cellular uptake by interacting with SR-B1. Alternatively, LDL-associated cholesterol can be captured and internalized in coated endocytic vesicles in a LDLR-mediated fashion. Intracellular cholesterol excess is converted into cholesteryl esters by ACAT1 and stored into lipid droplets. Cellular cholesterol efflux is mainly controlled by ABCA1 and ABCG1, two regulatory proteins belonging to the ATP-binding cassette transporter superfamily. Cellular cholesterol homeostasis is maintained by sterol-sensitive systems, such as SREBP2 and LXR. SREBP2-mediated adaptative response promotes cholesterol biosynthesis and uptake. Conversely, LXR promotes cholesterol excretion while impairing its uptake and production. PPARα activation promotes LXR-mediated ABCA1 expression and blocks cholesterol biosynthesis by inhibiting SREBP2. (B) Pharmacological targeting of de novo cholesterol biosynthesis pathway. Statins target and inhibit the activity of the rate-limiting enzyme HMGCR. Ro 48-8071 and Zaragozic acid act downstream of the mevalonate pathway, by inhibiting the activity of SQS and OSC, respectively. (C) Pharmacological targeting of cholesterol efflux and storage. The PPARα agonist Fenofibrate promotes PPARα-RXR interaction, thereby activating the PPARα signaling cascade. Both synthetic (CP-113818, Avasimibe, Avasimin) and natural (Bitter melon extract) inhibitors of ACAT-1 block cholesterol esterification and intracellular overload. (D) Pharmacological targeting of cholesterol homeostasis. LXR agonists, such as GW3965, T0901317, 22(R)-hydroxycholesterol and LXR623, can activate LXR signaling cascade, leading to increased cholesterol efflux and reduced cholesterol uptake. HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; SQS, Squalene synthase; SQLE, Squalene epoxidase; OSC, 2,3-oxidosqualene cyclase; SR B1, scavenger receptor type B class 1; LDLR, LDL receptor; ACAT1, Acetyl-CoA Acetyltransferase 1. PPAR- α, peroxisome proliferator-activated receptor; LXR, liver X receptor; SREBP-2, sterol regulatory element-binding protein 2; ABCA1, ATP Binding Cassette Subfamily A Member 1; ABCG1, ATP Binding Cassette Subfamily G Member 1; HDL, High-density Lipoprotein; LDL, Low-density Lipoprotein.