Celecoxib activates a novel mitochondrial apoptosis signaling pathway.
The cyclooxygenase (COX)-2 inhibitor Celecoxib may inhibit cancer cell growth independently of its capacity to block the COX-2 enzyme. The growth inhibitory effect had been attributed to its pro-apoptotic effects. However, the molecular details of Celecoxib-induced apoptosis have not been analyzed yet. To differentiate between death receptor and mitochondrial signaling pathways, induction of apoptosis upon treatment with Celecoxib was tested in Jurkat T- and BJAB B-lymphoma cell lines with defects in either pathway. Celecoxib-induced dose- and time-dependent apoptosis in Jurkat and BJAB cells involving i) activation of caspases-9, -8, and -3, ii) cleavage of poly(ADP-ribose) polymerase and inhibitor of caspase-activated DNAase, iii) breakdown of the mitochondrial membrane potential, and iv) release of cytochrome c. Lack of Fas-associated death domain protein (FADD), overexpression of a dominant negative FADD, lack of caspase-8, and treatment with caspase-8-specific inhibitors had no influence on Celecoxib-induced apoptosis. In contrast, overexpression of a dominant negative caspase-9 or pharmacological inhibition of caspase-9 strongly interfered with Celecoxib-induced cell death. Furthermore, expression of Apaf-1 was required for Celecoxib-induced apoptosis. Importantly, Bcl-2 overexpression did not abrogate caspase activation, mitochondrial alterations, and apoptosis upon Celecoxib treatment while inhibiting radiation induced apoptosis. In conclusion, Celecoxib induces apoptosis via a novel apoptosome-dependent but Bcl-2-independent mitochondrial pathway.
Jendrossek
Verena
V
Department of Radiation Oncology, Experimental Radiotherapy Group, University of Tübingen, Hoppe Seyler Str. 3, D-72076 Tübingen, Germany.
Handrick
René
R
Belka
Claus
C
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D053453:Caspase 9; D020169:Caspases / Q000502:physiology; D000068579:Celecoxib; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D019169:Jurkat Cells; D007700:Kinetics; D008565:Membrane Proteins; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008954:Models, Biological; D011451:Prostaglandin-Endoperoxide Synthases; D011506:Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011720:Pyrazoles; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C506592:APAF1 protein, human; D000970:Antineoplastic Agents; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D018124:Receptors, Tumor Necrosis Factor; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C506433:CASP9 protein, human; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases; D000068579:Celecoxib