PMC

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.

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.