Aberrant Cholesterol Metabolism in Ovarian Cancer: Identification of Novel Therapeutic Targets

Abstract

Cholesterol is an essential substance in mammalian cells, and cholesterol metabolism plays crucial roles in multiple biological functions. Dysregulated cholesterol metabolism is a metabolic hallmark in several cancers, beyond the Warburg effect. Reprogrammed cholesterol metabolism has been reported to enhance tumorigenesis, metastasis and chemoresistance in multiple cancer types, including ovarian cancer. Ovarian cancer is one of the most aggressive malignancies worldwide. Alterations in metabolic pathways are characteristic features of ovarian cancer; however, the specific role of cholesterol metabolism remains to be established. In this report, we provide an overview of the key proteins involved in cholesterol metabolism in ovarian cancer, including the rate-limiting enzymes in cholesterol biosynthesis, and the proteins involved in cholesterol uptake, storage and trafficking. Also, we review the roles of cholesterol and its derivatives in ovarian cancer and the tumor microenvironment, and discuss promising related therapeutic targets for ovarian cancer.

Keywords: carcinogenesis; cholesterol metabolism; ovarian cancer; therapeutic targets; tumor microenvironment.

Figure 1

Schematic illustration of cholesterol metabolism homeostasis and potential drugs. (i)Cholesterol bio synthesis. (ii) Cholesterol uptake. (iii) Cholesterol storage. (iv) Cholesterol conversion. (v) Cholesterol efflux. (i) De novo cholesterol synthesis involves nearly 30 enzymatic reactions, in which HMGR and SQLE are two key rate-limiting enzymes. FPP and GGPP, intermediates in this process, contribute to the prenylation of RAS and Rho proteins, which is necessary for RAS and Rho signaling activation. (ii) Cholesterol uptake is mediated by LDL-LDLR binding, which is followed by endocytosis of LDL by cells. However, high cholesterol accumulation leads to intracellular lipo-toxicity. High intracellular cholesterol levels suppress SREBP2 transcription factor activity, thereby restricting the expression of enzymes involved in cholesterol synthesis or cholesterol uptake. (iii) Excess cholesterol is converted into cholesterol ester by SOAT1 enzyme, then stored in lipid droplets. (iv) Excess cholesterol is converted to oxysterol through multiple enzymatic or non-enzymatic process. (v) Oxysterol activates LXR-RXR signaling and results in expression of ABCA1, ABCG1, and IDOL, which promote the cholesterol efflux pathway.