CD437, a synthetic retinoid, induces apoptosis in human respiratory epithelial cells via caspase-independent mitochondrial and caspase-8-dependent pathways both up-regulated by JNK signaling pathway.
The synthetic retinoid-related molecule CD437-induced apoptosis in human epithelial airway respiratory cells: the 16HBE bronchial cell line and normal nasal epithelial cells. CD437 caused apoptosis in S-phase cells and cell cycle arrest in S phase. Apoptosis was abolished by caspase-8 inhibitor z-IETD-fmk which preserved S-phase cells but was weakly inhibited by others selective caspase-inhibitors, indicating that caspase-8 activation was involved. z-VAD and z-IETD prevented the nuclear envelope fragmentation but did not block the chromatin condensation. The disruption of mitochondrial transmembrane potential was also induced by CD437 treatment. The translocation of Bax to mitochondria was demonstrated, as well as the release of cytochrome c into the cytosol and of apoptosis-inducing factor (AIF) translocated into the nucleus. z-VAD and z-IETD did not inhibit mitochondrial depolarization, Bax translocation or release of cytochrome c and AIF from mitochondria. These results suggest that CD437-induced apoptosis is executed by two converging pathways. AIF release is responsible for chromatin condensation, the first stage of apoptotic cell, via a mitochondrial pathway independent of caspase. But final stage of apoptosis requires the caspase-8-dependent nuclear envelope fragmentation. In addition, using SP600125, JNK inhibitor, we demonstrated that CD437 activates the JNK-MAP kinase signaling pathway upstream to mitochondrial and caspase-8 pathways. Conversely, JNK pathway inhibition, which suppresses S-phase apoptosis, did not prevent cell cycle arrest within S phase, confirming that these processes are triggered by distinct mechanisms.
Boisvieux-Ulrich
Emmanuelle
E
Laboratoire de Cytophysiologie et Toxicologie Cellulaire, Université Paris7, Denis Diderot, case 70-73,2 place Jussieu, 75251 Paris Cedex 05, France. boisvieux@paris7.jussieu.fr
Sourdeval
Matthieu
M
Marano
Francelyne
F
D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D018929:Cell Culture Techniques; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D008954:Models, Biological; D009831:Olfactory Mucosa / Q000166:cytology / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology*; D012176:Retinoids / Q000378:metabolism / Q000494:pharmacology*; D016196:S Phase; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects*; D051028:bcl-2-Associated X Protein
D000873:Anthracenes; C494826:BAX protein, human; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012176:Retinoids; D051028:bcl-2-Associated X Protein; C432165:pyrazolanthrone; D045304:Cytochromes c; D048031:JNK Mitogen-Activated Protein Kinases; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases