Cisplatin-induced apoptosis in auditory cells: role of death receptor and mitochondrial pathways.
Cisplatin, a commonly used chemotherapeutic agent, has a major limitation due to its ototoxicity. Previous studies have shown that cisplatin induces apoptosis in auditory sensory cells, but the underlying mechanisms remain to be elucidated. In this study, cisplatin was found to induce apoptosis in a cochlear cell line, in a dose- and duration-dependent manner. Specific caspase assays revealed an early (6 h) but transient increase in caspase 8 activity, and a delayed (12 h) increase in caspase 9 activity. The enhanced caspase 8 activity was preceded by upregulation of p53 expression, and coincided with cleavage of Bid to its truncated form. This was followed temporally by activation and mitochondrial translocation of Bax, induction of mitochondrial permeability transition, release of cytochrome c into the cytosol, activation of caspase 9, and entry into the execution phase of apoptosis. Our results indicate the involvement of both the death receptor mechanisms as well as mitochondrial pathways in cisplatin-induced apoptosis of auditory cells in an in vitro model system.
Devarajan
Prasad
P
Division of Nephrology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY 10467, USA. prasad.devarajan@chmcc.org
Savoca
Michelle
M
Castaneda
M Patricia
MP
Park
Moon Soo
MS
Esteban-Cruciani
Nora
N
Kalinec
Gilda
G
Kalinec
Federico
F
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000737:chemistry / Q000187:drug effects; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D003051:Cochlea / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D013997:Time Factors; D014018:Tissue Distribution; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins; D003574:Cytochrome c Group; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D002945:Cisplatin