Abstract
Peroxisome proliferator-activated receptor (PPAR)-γ ligands have been shown to inhibit human lung cancers by inducing apoptosis and differentiation. In the present study, we elucidated the apoptotic mechanism of PPARγ activation in human lung cancers by using a novel PPARγ agonist, 1-(trans-methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-(1H-indene-2-carboxylic acid ethyl ester (KR-62980), and rosiglitazone. PPARγ 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 PPARγ 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 PPARγ-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 PPARγ antagonist, and by knockdown of PPARγ expression, indicating the involvement of PPARγ in these actions. The results of the present study suggest that PPARγ activation induces apoptotic cell death in non–small-cell lung carcinoma mainly through ROS formation via POX induction.
Footnotes
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This research was supported by a grant from the Center for Biological Modulators of the 21st Century Frontier R&D Program, The Ministry of Science and Technology, Korea.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.107.035584.
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ABBREVIATIONS: NSCLC, non–small-cell lung cancer(s); PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; POX, proline oxidase; KR-62980, 1-(trans-methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-(1H-indene-2-carboxylic acid ethyl ester; BADGE, bisphenol A diglycidyl ether; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; 15d-PGJ2, 15-deoxy-Δ12,14-prostaglandin-J2; RNAi, RNA interference; DCFH, 2′,7′-dichlorodihydrofluorescein; DMEM, Dulbecco's modified Eagle's medium; RT-PCR, reverse transcription-polymerase chain reaction.
- Received March 2, 2007.
- Accepted May 29, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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