Apoptotic action of peroxisome proliferator-activated receptor-gamma 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 PPARgamma activation in human lung cancers by using a novel PPARgamma agonist, 1-(trans-methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-(1H-indene-2-carboxylic acid ethyl ester (KR-62980), and rosiglitazone. PPARgamma 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 PPARgamma 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 PPARgamma-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 PPARgamma antagonist, and by knockdown of PPARgamma expression, indicating the involvement of PPARgamma in these actions. The results of the present study suggest that PPARgamma activation induces apoptotic cell death in non-small-cell lung carcinoma mainly through ROS formation via POX induction.
Kim
Ki Young
KY
Center for Metabolic Syndrome Therapeutics, Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Korea.
Ahn
Jin Hee
JH
Cheon
Hyae Gyeong
HG
D017209:Apoptosis / Q000502:physiology*; D001559:Benzhydryl Compounds; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000494:pharmacology; D005562:Formazans / Q000378:metabolism; D006801:Humans; D007192:Indenes / Q000494:pharmacology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011394:Proline Oxidase / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000077154:Rosiglitazone; D013778:Tetrazolium Salts / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D004852:Epoxy Compounds; D005562:Formazans; D007192:Indenes; D009025:Morpholines; D047495:PPAR gamma; D011394:Proline Oxidase; D017382:Reactive Oxygen Species; D000077154:Rosiglitazone; D013778:Tetrazolium Salts; D045162:Thiazolidinediones; C513115:1-(methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-1H-indene-2-carboxylic acid ethyl ester; C079782:MTT formazan; C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds