title: Proteomic analysis of the balance between survival and cell death responses in cisplatin-mediated ototoxicity.
abstract: Cisplatin, a widely used anticancer drug, preferentially damages outer hair cells (OHCs) of the inner ear. In this study, an antibody microarray was used to identify early changes in protein expression in the rat cochlea induced by cisplatin. Only small changes in hearing thresholds (4-34 dB elevation) were detected two days after cisplatin treatment (12 mg/kg). OHC function, measured by otoacoustic emissions, was slightly depressed (10 dB), and little or no receptor cell loss was observed. However, cisplatin induced large changes in the expression of 19 proteins involved in apoptosis, cell survival, or progression through the cell cycle. Fifteen of the proteins are novel to the study of the inner ear. Immunoblotting confirmed increases in the levels of the pro-survival activating transcription factor 2 (ATF2), of pro-apoptotic serine-threonine protein kinase, receptor interacting protein, and a 70/75 kDa nitrotyrosine bearing doublet of unknown function. Anti-nitrotyrosine antibodies localized these oxidatively damaged proteins to the stereocilia of OHCs, the Golgi-centrosome region of Hensen's cells, nuclei of outer pillar cells, and tunnel crossing fibers innervating OHCs. The results of this proteomic analysis reflect the commencement of ototoxic and cell survival responses before the observation of a significant functional or anatomical loss.
authors.affiliation: Center for Hearing and Deafness, Department of Anesthesiology, Pathology, and Microbiology and Immunology, University at Buffalo, the State University of New York, Buffalo, NY 14214, USA.
authors.forename: Samson
authors.initials: S
authors.lastname: Jamesdaniel
authors.forename: Dalian
authors.initials: D
authors.lastname: Ding
authors.forename: Mohammad Habiby
authors.initials: MH
authors.lastname: Kermany
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Davidson
authors.forename: Paul R
authors.initials: PR
authors.lastname: Knight
authors.forename: Richard
authors.initials: R
authors.lastname: Salvi
authors.forename: Donald E
authors.initials: DE
authors.lastname: Coling
mesh_terms: D000818:Animals; D000906:Antibodies; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D007758:Ear, Inner / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016057:Evoked Potentials, Auditory, Brain Stem; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects; D008297:Male; D040081:Protein Array Analysis; D020543:Proteome / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013045:Species Specificity
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D020543:Proteome; D002945:Cisplatin