Metabolic alterations and targeted therapies in prostate cancer.
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.
Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Richard
R
Flavin
Giorgia
G
Zadra
Massimo
M
Loda
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use; D020536:Enzyme Activators / Q000627:therapeutic use; D064429:Fatty Acid Synthases / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis / Q000502:physiology; D008297:Male; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology*; D015398:Signal Transduction / Q000502:physiology
D000970:Antineoplastic Agents; D020536:Enzyme Activators; D064429:Fatty Acid Synthases; D055372:AMP-Activated Protein Kinases