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.

Figure 1

AMPK controls the main metabolic pathways in PCa cells. PCa cells are characterized by exacerbation of lipogenesis associated with hyperactivation of the mTOR pathway. Physiological and pharmacological activation of AMPK by LKB1/CaMKK and AMPK activators, respectively, can inhibit these pathways by direct phosphorylation of key lipogenic enzymes (ACC, in particular isoform 1, HMG-CoA reductase) and key kinases (the complex TSC1/TSC2 and the mTOR-associated factor Raptor) or by regulating transcription through SREBP1c. Black and red arrows indicate activation and inhibition, respectively. Tumour suppressor genes are represented in violet boxes. AMPK, AMP-activated protein kinase; CaMKK, calmodulin-dependent protein kinase kinase; SREBP1c, sterol regulatory element binding protein-1c; ACLY, ATP citrate lyase; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; HMG-CoA reductase, 3-hydroxy-3-methyl-glutaryl-CoA reductase; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin homologue; TSC2/TSC1, tuberous sclerosis complex 1/2; RHEB, Ras homologue enriched in brain; mTOR, mammalian target of rapamycin; 4EBP1, 4E-binding protein 1; S6K1, S6 kinase 1; eiF4E, eukaryotic translation initiation factor 4E.

Figure 2

The central role of FASN in PCa fatty acid metabolism. FASN 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. Dysregulation of lipogenesis is associated with over-expression of FASN in PCa cells. ACoA, acetyl CoA; ACC, acetyl-CoA carboxylase; ATP, adenosine triphosphate; FASN, fatty acid synthase; MCoA, malonyl-CoA; SREBP1c, sterol regulatory element binding protein-1c.