Bisphenol A diglycidyl ether-induced apoptosis involves Bax/Bid-dependent mitochondrial release of apoptosis-inducing factor (AIF), cytochrome c and Smac/DIABLO.
(1) Bisphenol A diglycidyl ether (BADGE) is a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) antagonist, which is able to induce apoptosis in tumor cells independently of PPAR-gamma in caspase-dependent and -independent manners. Additionally, BADGE promotes TRAIL-induced apoptosis. (2) We report that BADGE activates via Bax and caspases-2 and -8 both the intrinsic and extrinsic apoptotic pathways using Bid as a shunt. (3) BADGE stimulates the mitochondrial release of apoptosis-inducing factor (AIF), cytochrome c and second mitochondria-derived activator of caspase/direct IAP-binding protein with low pl (Smac/DIABLO). The release of cytochrome c could not be blocked by inhibitors of caspases-3, -8 and -9 indicating that BADGE acts upstream of caspases-3 and -9 and does not involve caspase-8 to release cytochrome c. (4) While the caspase-independent apoptotic effect might be mediated by AIF, the sensitizing effect of BADGE against other apoptotic substances is most likely mediated by the X-linked inhibitor of apoptosis inhibitor Smac/DIABLO. (5) Our data suggest that BADGE or BADGE derivatives could represent promising substances for the treatment of neoplasms improving the antitumoral activity of TRAIL.
Fehlberg
Sebastian
S
Clinical Research Unit for Gastrointestinal Endocrinology, University of Marburg, Baldingerstrasse, Marburg 35033, Germany.
Gregel
Cornelia M
CM
Göke
Alexandra
A
Göke
Rüdiger
R
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D001559:Benzhydryl Compounds; D002352:Carrier Proteins / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology*; D005420:Flavoproteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D000098826:Bisphenol A Compounds
D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D001559:Benzhydryl Compounds; D002352:Carrier Proteins; D045304:Cytochromes c; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005420:Flavoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C494829:AIFM1 protein, human; C494826:BAX protein, human; C494814:BID protein, human; C412403:DIABLO protein, human; C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds