Targeting lipid metabolism in the treatment of ovarian cancer

Abstract

Cancer cells undergo alterations in lipid metabolism to support their high energy needs, tumorigenesis and evade an anti-tumor immune response. Alterations in fatty acid production are controlled by multiple enzymes, chiefly Acetyl CoA Carboxylase, ATP-Citrate Lyase, Fatty Acid Synthase, and Stearoyl CoA Desaturase 1. Ovarian cancer (OC) is a common gynecological malignancy with a high rate of aggressive carcinoma progression and drug resistance. The accumulation of unsaturated fatty acids in ovarian cancer supports cell growth, increased cancer cell migration, and worse patient outcomes. Ovarian cancer cells also expand their lipid stores via increased uptake of lipids using fatty acid translocases, fatty acid-binding proteins, and low-density lipoprotein receptors. Furthermore, increased lipogenesis and lipid uptake promote chemotherapy resistance and dampen the adaptive immune response needed to eliminate tumors. In this review, we discuss the role of lipid synthesis and metabolism in driving tumorigenesis and drug resistance in ovarian cancer conferring poor prognosis and outcomes in patients. We also cover some aspects of how lipids fuel ovarian cancer stem cells, and how these metabolic alterations in intracellular lipid content could potentially serve as biomarkers of ovarian cancer.

Keywords: biomarkers; fatty acid; lipid metabolism; microenvironment; ovarian cancer.

Figure 1. Fatty acid metabolism in cancer.

Gene alterations: Several gene alterations (mutations, amplifications, deletions) contribute to increased production of lipogenic genes either directly via transcription regulation, or indirectly by loss of repressors. Lipid uptake: Fatty acids (FAs) are obtained via de novo lipogenesis and exogenous uptake. FA translocase CD36 is responsible for the exogenous uptake of FAs from the surrounding microenvironment. These FAs can be converted to triacylglycerols (DGAT1) and stored in lipid droplets or used in generation of acetyl-CoA through β-oxidation. Lipid Synthesis: Glucose is a major carbon source for de novo lipogenesis. Pyruvate derived from glucose contributes the substrate for several lipogenic enzymes (ACLY, ACC, FASN, SCD-1) leading to an increased lipid pool. Lipid breakdown: Lipid droplets are mobilized by lipase enzymes (MAGL) to provide energy for cancer cell growth and secondary bioactive lipids that modify the tumor microenvironment. Several promising lipid-targeting anti-cancer therapies are based on disrupting the lipid metabolic pathways (enzymes, receptors, and bioactive lipids) that are shown in this figure. Created with https://biorender.com.