Activation of peroxisome proliferator-activated receptor γ contributes to the survival of T lymphoma cells by affecting cellular metabolism

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a metabolic regulator involved in maintaining glucose and fatty acid homeostasis. Besides its metabolic functions, the receptor has also been implicated in tumorigenesis. Ligands of PPAR gamma induce apoptosis; in several types of tumor cells, leading to the proposal that these ligands may be used as antineoplastic agents. However, apoptosis induction requires high doses of ligands, suggesting the effect may not be receptor-dependent. In this report, we show that PPAR gamma is expressed in human primary T-cell lymphoma tissues and activation of PPAR gamma with low doses of ligands protects lymphoma cells from serum starvation-induced apoptosis. The prosurvival effect of PPAR gamma was linked to its actions on cellular metabolic activities. In serum-deprived cells, PPAR gamma attenuated the decline in ATP, reduced mitochondrial hyperpolarization, and limited the amount of reactive oxygen species (ROS) in favor of cell survival. Moreover, PPAR gamma regulated ROS through coordinated transcriptional control of a set of proteins and enzymes involved in ROS metabolism. Our study identified cell survival promotion as a novel activity of PPAR gamma. These findings highlight the need for further investigation into the role of PPAR gamma in cancer before widespread use of its agonists as anticancer therapeutics.