Inhibition of Cancer Cell Proliferation by PPARγ Is Mediated by a Metabolic Switch that Increases Reactive Oxygen Species Levels

The nuclear receptor peroxisome-proliferation-activated receptor gamma(PPAR gamma), a transcriptional master regulator of glucose and lipid metabolism, inhibits the growth of several common cancers, including lung cancer. In this study, we show that the mechanism by which activation of PPAR gamma inhibits proliferation of lung cancer cells is based on metabolic changes. We found that treatment with the PPAR gamma agonist pioglitazone triggers a metabolic switch that inhibits pyruvate oxidation and reduces glutathione levels. These PPAR gamma-induced metabolic changes result in a marked increase of reactive oxygen species (ROS) levels that lead to rapid hypophosphorylation of retinoblastoma protein (RB) and cell-cycle arrest. The antiproliferative effect of PPAR gamma activation can be prevented by suppressing pyruvate dehydrogenase kinase 4 (PDK4) or beta-oxidation of fatty acids in vitro and in vivo. Our proposed mechanism also suggests that metabolic changes can rapidly and directly inhibit cell-cycle progression of cancer cells by altering ROS levels.