Dysregulated lipid metabolism in cancer

Figure 1 Signaling pathways regulating lipogenesis in cancer cells. This scheme represents the main regulation of lipogenesis in cancer cells. Lipid metabolizing enzymes are regulated by oncogenic signals. Growth factor-activated PI3K-AKT or hypoxia-induced HIF stimulates glucose transporters and hexokinases to promote glycolysis, providing more synthetic precursors for fatty acid synthesis. Akt also activates the lipogenic enzyme activity and expression through direct phosphorylation or SREBP-mediated transcription enhancement of lipogenic genes. The tumor suppressor, p53, plays a role in glucose uptake, pentose phosphate pathway and anaplerosis of citrate. As a transcription factor, p53 also enhances the expression of glucose transporters and Glutaminase 2. The inductive effect on TIGAR and the activity inhibition of G6PDH caused by catalytic effect of p53 constitute a complex regulation on pentose phosphate pathway imposed by p53. LKB1/AMPK pathway, the master regulator in cellular energetic metabolism, modulates ACC activity either by direct phosphorylation or through SREBP-1. Myc is involved in lipid metabolism and promotes citrate anaplerosis through increasing glutamine transporters and glutaminase 2 expression. The activity and expression of lipogenic enzyme, ACL, ACC and FASN, are regulated at multiple levels through mTOR, MAPK, USP2a, Sp1, etc. Glut: Glucose transporter; HK: Hexokinase; G-6-P: Glucose-6-phosphate; F-6-P: Fructose-6-phosphate; FBP: Fructose-1,6-bisphosphate; GFR: Growth factors receptor; PI3K: Phosphatidylinositol 3-kinase; MAPK: Mitogen activated protein kinase; SREBP-1: Sterol-regulatory element-binding protein-1; TIGAR: TP53-induced glycolysis and apoptosis regulator; OAA: Oxaloacetate; ACL: ATP citrate lyase; ACC: Acetyl-CoA carboxylase; FASN: Fatty acid synthase; FA: Fatty acids; G6PDH: Glucose-6-phosphate dehydrogenase; αKG: α-ketoglutarate; PFK: Phosphofructokinase; NADPH: Nicotinamide adenine dinucleotide phosphate; Mal: Malate; ME: Malic enzyme; Ac-CoA: Acetyl-CoA; mTOR: Mammalian target of rapamycin; USP2a: Ubiquitin-specific protease-2a; IDH3: Isocitrate dehydrogenase 3; R-5-P: Ribose-5-phosphate; HIF: Hypoxia-inducible factor; EMS: Extracellular microenvironmental stress.