Cisplatin-induced apoptosis of DRG neurons involves bax redistribution and cytochrome c release but not fas receptor signaling.
Cisplatin causes apoptosis of DRG neurons in vitro and in vivo that can be prevented by high dose NGF. Design of a neuronal rescue strategy for patients receiving cisplatin will be facilitated by knowledge of the mechanism by which cisplatin causes DRG death. Inhibition of the fas receptor/ligand interaction prevents apoptosis in certain cancer cell lines treated with DNA damaging agents, including cisplatin. We demonstrated that killing curves from mice lacking a functional fas receptor and wild-type controls were not different over a wide range of therapeutically relevant concentrations. However, cisplatin treatment of DRG caused redistribution of cytosolic bax and mitochondrial release of cytochrome c. Bax redistribution was prevented by high dose NGF. This demonstrates for the first time that cisplatin does not signal for death via the fas pathway, but it does initiate the mitochondrial stress pathway in neurons and that NGF blocks death upstream of bax redistribution.
McDonald
Elizabeth S
ES
Molecular Neuroscience Program, Mayo Graduate School, Rochester, Minnesota 55905, USA.
Windebank
Anthony J
AJ
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D003574:Cytochrome c Group / Q000378:metabolism*; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D053222:Fas Ligand Protein; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D000970:Antineoplastic Agents; C494826:BAX protein, human; C494827:Bax protein, mouse; C494828:Bax protein, rat; D003574:Cytochrome c Group; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D020932:Nerve Growth Factor; D002945:Cisplatin