METABOLIC RE-PROGRAMMING IN CANCER CELLS: LIPOGENESIS, OXIDATIVE STRESS, AND THE MITOCHONDRIAL CONNECT

Mitochondrial metabolic re-modeling in cancer cells re-routes the glycolytic intermediates to biosynthetic reactions (instead of the physiological oxidative-phosphorylation fate).1 One such effect is the neoplastic activation of lipid biosynthesis. Lipogenic activation in cancer cells endows them with exceptional growth advantage through high membrane lipids turnover and lipid-rafts, mitochondrial redox-energy homeostasis, oncogenic signaling activation, pro-apoptotic pathway suppression, drug resistance and cancer cell stemness.2 This presentation will demonstrate the association of abnormal lipogenesis (catalysed by fatty acid synthase, FASN) with altered redox-energy balance and cancer cell proliferation. Using the ocular cancer model of retinoblastoma, experimental and clinical correlations between abnormal fatty acid metabolism, lipid peroxidation, aberrant cell cycle and apoptotic regulation, cell invasion and metastasis, will be discussed.  While lipogenesis is largely linked with the cytosolic FASN I, there exists its lesser studied, structurally-distinct mitochondrial counterpart, FASN II (or mtFASN).3 What are the functional roles of mtFASN in human cancer cells? Is there a regulatory connect between cytoplasmic and mitochondrial FASN?  Insights from global gene profiling and biochemical analyses using FASN enzyme inhibitors4 and FASN gene-silencing,5 will be presented.