Apoptotic action of peroxisome proliferator-activated receptor-γ activation in human non-small-cell lung cancer is mediated via proline oxidase-induced reactive oxygen species formation

Peroxisome proliferator- activated receptor ( PPAR)- gamma ligands have been shown to inhibit human lung cancers by inducing apoptosis and differentiation. In the present study, we elucidated the apoptotic mechanism of PPAR gamma activation in human lung cancers by using a novel PPAR agonist, 1-( trans- methyliminoN- oxy)- 6-( 2- morpholinoethoxy)- 3- phenyl-( 1H- indene- 2carboxylic acid ethyl ester ( KR- 62980), and rosiglitazone. PPAR gamma activation selectively inhibited cell viability of non small- cell lung cancer with little effect on small- cell lung cancer and normal lung cells. The cell death induced by PPAR gamma activation presented apoptotic features of oligonucleosomal DNA fragmentation in A549 human non - small- cell lung cancer cell line. Reactive oxygen species ( ROS) production was accompanied by increased expression of proline oxidase ( POX), a redox enzyme expressed in mitochondria, upon incubation with the agonists. POX RNA interference treatment blocked PPAR gamma induced ROS formation and cytotoxicity, suggesting that POX plays a functional role in apoptosis through ROS formation. The apoptotic effects by the agonists were antagonized by bisphenol A diglycidyl ether, a PPAR gamma antagonist, and by knockdown of PPAR gamma expression, indicating the involvement of PPAR gamma in these actions. The results of the present study suggest that PPAR gamma activation induces apoptotic cell death in non - smallcell lung carcinoma mainly through ROS formation via POX induction.