Metabolic alterations and targeted therapies in prostate cancer

Abstract

Cancer cells synthesize de novo large amounts of fatty acids and cholesterol, irrespective of the circulating lipid levels and benefit from this increased lipid synthesis in terms of growth advantage, self-survival and drug resistance. Key lipogenic alterations that commonly occur in prostate cancer include over-expression of the enzyme fatty acid synthase (FASN) and deregulation of the 5-AMP-activated protein kinase (AMPK). FASN is a key metabolic enzyme that catalyses the synthesis of palmitate from the condensation of malonyl-CoA and acetyl-CoA de novo and plays a central role in energy homeostasis, by converting excess carbon intake into fatty acids for storage. AMPK functions as a central metabolic switch that governs glucose and lipid metabolism. Recent interest has focused on the potential of targeting metabolic pathways that may be altered during prostate tumorigenesis and progression. Several small molecule inhibitors of FASN have now been described or in development for therapeutic use; in addition, drugs that directly or indirectly induce AMPK activation have potential benefit in prostate cancer prevention and treatment.