Cisplatin-induced Ototoxicity Is Mediated by Nitroxidative Modification of Cochlear Proteins Characterized by Nitration of Lmo4

Jamesdaniel, Samson; Coling, Donald; Hinduja, Sneha; Ding, Dalian; Li, Jun; Cassidy, Linda; Seigel, Gail M.; Qu, Jun; Salvi, Richard

doi:10.1074/jbc.m111.297960

Cited by 38 publications

(64 citation statements)

References 53 publications

(63 reference statements)

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“…The ototoxic side effects of cisplatin have been well documented (6,7,9). Consistent with previous reports, a 16 mg/kg dose of cisplatin induced a significant shift in distortion product amplitudes (Fig.…”

Section: Cisplatin-induced Ototoxicitysupporting

confidence: 79%

“…The sections were blocked and incubated in anti-SNitroso-Cysteine (1:200) for 2 h followed by 1 h incubation in biotinylated secondary antibody (Vector Laboratories, Burlingame, CA). The sections were then treated with avidin and biotin (Elite ABC-kit; Vector Laboratories) to facilitate immunodetection with 0.05% DAB stain (7).…”

Section: Methodsmentioning

confidence: 99%

“…The susceptibility of these cochlear regions to cisplatin ototoxicity has been well documented (9). Particularly, the organ of Corti consists of the key sensory receptor cells, the OHC, which is susceptible to cisplatin-induced functional as well as morphological loss, as demonstrated by DPOAEs and cochleograms (7). The localization of S-nitrosylated proteins in the cells of these highly sensitive cochlear regions that are known targets of cisplatin ototoxicity supports the significance of S-nitrosylation in cisplatin-mediated ototoxicity.…”

Section: Localization Of S-nitrosylated Proteins In Sensitive Cochleamentioning

confidence: 99%

“…Collectively, these findings highlight the importance of nitrosative stress and indicate the significance of cochlear protein S-nitrosylation in cisplatin-mediated ototoxicity. chlear Lmo4, a potential biomarker of cisplatin-induced oxidative damage of the inner ear (7). Cisplatin-induced nitrosylation of Bcl 2 , a proto-oncogene and p53, a transcriptional factor that regulates apoptosis, has been characterized in nonauditory cells (2,4).…”

Section: Innovationmentioning

confidence: 99%

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Is S-nitrosylation of Cochlear Proteins a Critical Factor in Cisplatin-Induced Ototoxicity?

Jamesdaniel

Manohar

Hinduja

2012

Antioxidants & Redox Signaling

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S-nitrosylation is a redox-sensitive protein modification, which is a highly specific, but reversible mechanism that regulates several signal transduction cascades. Oxidative stress plays a causal role in the ototoxic effects of an antineoplastic drug, cisplatin. Despite emerging evidence implicating nitroxidative stress as a critical factor in cisplatin toxicity, the significance of the cochlear protein S-nitrosylation in cisplatin ototoxicity is yet to be understood. In the present study, a 16-mg/kg dose of cisplatin, induced a significant shift in the amplitudes of distortion product otoacoustic emissions, a measure of outer hair cell activity, in Wistar rats, 3 days post-treatment. These ototoxic effects were accompanied by significant increases in the S-nitrosylation of at least three cochlear proteins. Biological significance of these S-nitrosylated proteins was indicated by their immunolocalization in organ of Corti, stria vascularis, and spiral ganglions, which are known cochlear targets of cisplatin toxicity. In addition, co-treatment with Trolox, an inhibitor of peroxynitrite, attenuated cisplatin-induced S-nitrosylation of cochlear proteins and prevented the associated hearing loss. The cisplatin-induced S-nitrosylation of inner ear proteins, their sensitive cochlear localization, and their potential association with cisplatin-induced hearing loss suggests that S-nitrosylation of cochlear proteins might play a crucial role in mediating cisplatin ototoxicity. Antioxid. Redox Signal. 17, 929-933.

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Section: Cisplatin-induced Ototoxicitysupporting

confidence: 79%

Section: Methodsmentioning

confidence: 99%

Section: Localization Of S-nitrosylated Proteins In Sensitive Cochleamentioning

confidence: 99%

Section: Innovationmentioning

confidence: 99%

See 2 more Smart Citations

Is S-nitrosylation of Cochlear Proteins a Critical Factor in Cisplatin-Induced Ototoxicity?

Jamesdaniel

Manohar

Hinduja

2012

Antioxidants & Redox Signaling

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“…Like ROS, RNS acts on various targets in the cell, causing cytotoxicity, although its mechanisms are less clear than ROS. In the cochlea, it has been reported that cisplatin nitrates LIM domain only 4 (Lmo4), a transcriptional regulator controlling cell survival and cell death (Jamesdaniel et al., 2012). …”

Section: Cisplatin and Other Platinum Compoundsmentioning

confidence: 99%

An integrated view of cisplatin-induced nephrotoxicity and ototoxicity

2015

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Cisplatin is one of the most widely-used drugs to treat cancers. However, its nephrotoxic and ototoxic side-effects remain major clinical limitations. Recent studies have improved our understanding of the molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. While cisplatin binding to DNA is the major cytotoxic mechanism in proliferating (cancer) cells, nephrotoxicity and ototoxicity appear to result from toxic levels of reactive oxygen species and protein dysregulation within various cellular compartments. In this review, we discuss molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. We also discuss potential clinical strategies to prevent nephrotoxicity and ototoxicity and their current limitations.

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CRISPR/Cas9‐mediated knockout of Lim‐domain only four retards organ of Corti cell growth

Rathinam

Rosati

Jamesdaniel

2018

J of Cellular Biochemistry

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Lim-domain only 4 (LMO4) plays a critical role in mediating the ototoxic side-effects of cisplatin, a highly effective anti-cancer drug. However, the signaling mechanism by which cochlear LMO4 mediates otopathology is yet to be fully understood. Knockout cell culture models are useful tools for investigating the functional roles of novel genes and delineating associated signaling pathways. Therefore, LMO4 knockout organ of Corti cells were generated by using the CRISPR (clustered regularly interspersed short palindromic repeats)/Cas9 (CRISPR-associated protein 9) system. Successful knockout of LMO4 in UB/OC1 cells was verified by the absence of LMO4 protein bands in immunoblots. Though the Knockout of LMO4 retarded the growth rate and the migratory potential of the cells it did not inhibit their long-term viability as the LMO4 knockout UB/OC1 cells were able to survive, proliferate, and form colonies. In addition, the knockout of LMO4 did not alter the expression of myosin VIIa, a biomarker of hair cells, suggesting that the knockout cells retain important characteristic features of cochlear sensory receptor cells. Thus, the findings of this study indicate that CRISPR/Cas9 system is a simple and versatile method for knocking out genes of interest in organ of Corti cells and that LMO4 knockout UB/OC1 cells are viable experimental models for studying the functional role of LMO4 in ototoxicity.

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Cisplatin-induced Ototoxicity Is Mediated by Nitroxidative Modification of Cochlear Proteins Characterized by Nitration of Lmo4

Cited by 38 publications

References 53 publications

Is S-nitrosylation of Cochlear Proteins a Critical Factor in Cisplatin-Induced Ototoxicity?

Is S-nitrosylation of Cochlear Proteins a Critical Factor in Cisplatin-Induced Ototoxicity?

An integrated view of cisplatin-induced nephrotoxicity and ototoxicity

CRISPR/Cas9‐mediated knockout of Lim‐domain only four retards organ of Corti cell growth

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