Lipid Metabolism and Endocrine Resistance in Prostate Cancer, and New Opportunities for Therapy

Abstract

Prostate cancer (PCa) is the most common cancer in men, and more than 10% of men will be diagnosed with PCa during their lifetime. Patients that are not cured with surgery or radiation are largely treated with endocrine therapies that target androgens or the androgen receptor (AR), a major driver of PCa. In response to androgen deprivation, most PCas progress to castrate resistant PCa, which is treated with anti-androgens like enzalutamide, but tumors still progress and become incurable. Thus, there is a critical need to identify cellular pathways that allow tumors to escape anti-androgen therapies. Epidemiological studies suggest that high-fat diets play important roles in PCa progression. Lipid metabolism rewires the PCa metabolome to support growth and resistance to endocrine therapies, although the exact mechanisms remain obscure. Therapeutic effects have been observed inhibiting several aspects of PCa lipid metabolism: Synthesis, uptake, and oxidation. Since AR remains a driver of PCa in advanced disease, strategies targeting both lipid metabolism and AR are starting to emerge, providing new opportunities to re-sensitize tumors to endocrine therapies with lipid metabolic approaches.

Keywords: AR; CPT1A; FASN; anti-androgens; combination therapy; dietary lipids; endocrine resistance; lipid oxidation; lipid synthesis; prostate cancer.

Figure 1

Cross-talk between lipid metabolism and the androgen receptor (AR) in the nucleus. The dotted arrows represent unknown mechanisms connecting fat burning in the mitochondria via CPT1A (carnitine palmitoyltransferase 1A) and fat synthesis in the cytoplasm via the FASN (fatty acid synthase) enzyme. Solid black arrows show direct connections. Red labels and red T-bars represent inhibitory drugs that are used in the clinic. Etomoxir and C75 are not used in humans. This diagram shows some of the sources of fatty acids available to the mitochondria, including the lipids that are newly synthesized via FASN. Light blue arrows show the substrates for FASN and its product, the fatty acid palmitate. This fatty acid of 16 carbons can be elongated and/or desaturated. The proportion of newly synthesized fatty acid that is burned in PCa is unknown, Dark blue arrows show that it can also be used for phospholipid and lipid droplet formation, which contains triglycerides and cholesterol esters. Exosomes delivering lipid droplets and phospholipids also represent another source of fatty acids for beta oxidation. Since androgens are known to regulate CPT1A and FASN enzyme activities, the coordination of fat synthesis and oxidation is likely modulated by the environmental context of the tumor, sometimes tipping the balance more towards synthesis and other times towards oxidation. Elucidating these tumor dependencies will increase the efficacy of lipid metabolic inhibitors and their combination with anti-androgen blockades.