Targeting nitrative stress for attenuating cisplatin-induced downregulation of cochlear LIM domain only 4 and ototoxicity

• Published in: Redox biology Vol. 10; no. C; pp. 257 - 265
• Main Authors: Jamesdaniel, Samson, Rathinam, Rajamani, Neumann, William L
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier 01.12.2016
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Antineoplastic Agents - toxicity; Apoptosis - drug effects; Cells, Cultured; Cisplatin; Cisplatin - toxicity; Cochlea; Cochlea - cytology; Cochlea - drug effects; Cochlea - metabolism; Disease Models, Animal; Down-Regulation - drug effects; Evoked Potentials, Auditory, Brain Stem; Hearing loss; Hearing Loss - chemically induced; Hearing Loss - metabolism; LIM Domain Proteins - metabolism; LMO4; Manganese Compounds - administration & dosage; Manganese Compounds - chemistry; Manganese Compounds - pharmacology; Membrane Proteins - metabolism; Mice; Mice, Inbred CBA; Ototoxicity; Peroxynitrous Acid - analogs & derivatives; Protein nitration; Research Paper; Serpins - metabolism; Signal Transduction - drug effects; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Cochlea; LMO4; Protein nitration; Cisplatin; Hearing loss; Ototoxicity
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2016.10.016

Cisplatin-induced ototoxicity remains a primary dose-limiting adverse effect of this highly effective anticancer drug. The clinical utility of cisplatin could be enhanced if the signaling pathways that regulate the toxic side-effects are delineated. In previous studies, we reported cisplatin-induced nitration of cochlear proteins and provided the first evidence for nitration and downregulation of cochlear LIM domain only 4 (LMO4) in cisplatin ototoxicity. Here, we extend these findings to define the critical role of nitrative stress in cisplatin-induced downregulation of LMO4 and its consequent ototoxic effects in UBOC1 cell cultures derived from sensory epithelial cells of the inner ear and in CBA/J mice. Cisplatin treatment increased the levels of nitrotyrosine and active caspase 3 in UBOC1 cells, which was detected by immunocytochemical and flow cytometry analysis, respectively. The cisplatin-induced nitrative stress and apoptosis were attenuated by co-treatment with SRI110, a peroxynitrite decomposition catalyst (PNDC), which also attenuated the cisplatin-induced downregulation of LMO4 in a dose-dependent manner. Furthermore, transient overexpression of LMO4 in UBOC1 cells prevented cisplatin-induced cytotoxicity while repression of LMO4 exacerbated cisplatin-induced cell death, indicating a direct link between LMO4 protein levels and cisplatin ototoxicity. Finally, auditory brainstem responses (ABR) recorded from CBA/J mice indicated that co-treatment with SRI110 mitigated cisplatin-induced hearing loss. Together, these results suggest that cisplatin-induced nitrative stress leads to a decrease in the levels of LMO4, downregulation of LMO4 is a critical determinant in cisplatin-induced ototoxicity, and targeting peroxynitrite could be a promising strategy for mitigating cisplatin-induced hearing loss.