Anticancer Properties of PPAR𝛼-Effects on Cellular Metabolism and Inflammation

Figure 1

PPARα interferes with the metabolic pathways in the cancer cells. In the state of energy deprivation, AMPK activates fatty acid oxidation through PPARα- and p53-dependent pathways and blocks anabolic processes, for example, cholesterol biosynthesis. AMPK is a potent inhibitor of Akt-induced glycolysis. In response to nutrient deficiency, PGC-1α and PPARα upregulate expression of TRB3, which inactivates Akt via direct interaction [29]. PPARα promotes fatty acid β-oxidation as a transcriptional activator of fatty acid catabolic enzymes and transport proteins (e.g., ACO, CPT1, UCP2, and UCP3). Simulateneously, PPARα blocks lipid synthesis by repression of SREBP-1 and -2, ACC, and FAS. FAS inhibition in various cancer types results in toxic accumulation of malonyl-CoA and apoptosis. For more details, see the text. Arrowheads represent activation/upregulation, and blunted lines indicate inhibition/downregulation of the cellular proteins or processes. ACC—acetyl-coA carboxylase; ACO—acyl-coA oxidase; AMPK—AMP-dependent kinase; CTP-1—carnitine palmitoyltransferase-1; FAS—fatty acid synthase; PGC-1α—PPARγ coactivator 1α; PUFA—polyunsaturated fatty acids; SREBP—steroid response element binding protein; TRB3—mammalian homolog of tribbles; UCP2, UCP3—uncoupling proteins.