Received for publication March 5, 2007.
Revised May 28, 2007.
Accepted for publication May 29, 2007.

Apoptotic action of PPAR activation in human non-small cell lung cancer is mediated via proline oxidase-induced ROS formation

Abstract

Peroxisome proliferator activated receptor- (PPAR) 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 activation in human lung cancers by using a novel PPAR agonist KR-62980 and rosiglitazone. PPAR 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 activation presented apoptotic features of oligonucleosomal DNA fragmentation in A549 human non-small cell lung cancer cell line. ROS production was accompanied by increased expression of proline oxidase (POX), a redox enzyme expressed in mitochondria, upon incubation with the agonists. POX RNAi treatment blocked PPAR-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 diaglycidyl ether, a PPAR antagonist and by knockdown of PPAR expression, indicating the involvement of PPAR in these actions. The results of the present study suggest that PPAR activation induces apoptotic cell death in non-small cell lung carcinoma mainly through ROS formation via POX induction.

Key words: PPARs, RNA/siRNA, Mechanisms of cell killing/apoptosis

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