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.
Highlights
Ovarian cancer is one of the most aggressive malignancies worldwide [1]
The cholesterol exported by ABC Subfamily A Member 1 (ABCA1) is loaded onto lipid-free apolipoprotein A-I, producing nascent high-density lipoprotein (HDL), which in turn is converted into mature HDL by lecithin:cholesterol acyltransferase (LCAT) in the plasma [33]
This liver X receptor (LXR)-RER heterodimer combined with co-activator binds LXR-responsive-elements (LXREs) in the nucleus and mediates the expression of cholesterol metabolism-related genes, such as ABCA1, ABCG1, and inducible degrader of LDL receptor (LDLR) (IDOL) [90]
Summary
Ovarian cancer is one of the most aggressive malignancies worldwide [1]. Due to the lack of obvious symptoms of early-stage ovarian cancer, newly diagnosed patients often present in advanced stages of disease, leading to the designation “silent killer” [2]. Other typical features of the tumor microenvironment include an insufficient supply of glucose and oxygen, which are non-beneficial for survival of tumor cells. To overcome this limitation, tumor cells and tumor-associated cells act in concert to develop reprogrammed adaptive metabolism [16]. Expressed proteins and enzymes involved in cholesterol metabolism promote ovarian cancer progression; cholesterol and its derivatives contribute to proliferation and chemoresistance in ovarian cancer and have roles in the immunosuppressive tumor microenvironment [22,23,24,25]. We have systematically summarized the most recent findings on cholesterol and its derivatives in ovarian cancer, with the aim of comprehensively understanding their specific functions to facilitate the identification of novel markers and therapeutic targets
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