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Nat. Commun., Published 12 September 2019, 10, Article number: 4150 | DOI https://doi.org/10.1038/s41467-019-12073-0 GSTA4 mediates reduction of cisplatin ototoxicity in female mice

Hyo-Jin Park^1,9, Mi-Jung Kim^1,9, Christina Rothenberger^1,9, Ashok Kumar², Edith M. Sampson³, Dalian Ding⁴, Chul Han¹, Karessa White¹, Kevin Boyd¹, Senthilvelan Manohar⁴, Yong-Hwan Kim⁵, Maria S. Ticsa¹, Aaron S. Gomez¹, Isabela Caicedo¹, Upal Bose¹, Paul J. Linser⁶, Takuya Miyakawa⁷, Masaru Tanokura⁷, Thomas C. Foster², Richard Salvi^4,8 & Shinichi Someya^1,*

¹ Department of Aging and Geriatric Research, University of Florida, Gainesville, FL 32611, USA.²Department of Neuroscience, University of Florida, Gainesville, FL 32611, USA. ³ Monoclonal Antibody Core, Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL 32610, USA.⁴ Center for Hearing and Deafness, State University of New York at Buffalo, Buffalo, NY 14214, USA. ⁵Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA.⁶ Whitney Laboratory, University of Florida, St. Augustine, FL 32080, USA. ⁷ Department of Applied Biological Chemistry, University of Tokyo, Yayoi, Tokyo 113-8657, Japan. ⁸Department of Audiology and Speech-Language Pathology, Asia University, Taichung, Taiwan 41354, Republic of China.⁹ These authors contributed equally: Hyo-Jin Park, Mi-Jung Kim, and Christina Rothenberger.

^*Correspondence and requests for materials should be addressed to S.S.

Abstract

Cisplatin is one of the most widely used chemotherapeutic drugs for the treatment of cancer. Unfortunately, one of its major side effects is permanent hearing loss. Here, we show that glutathione transferase α4 (GSTA4), a member of the Phase II detoxifying enzyme superfamily, mediates reduction of cisplatin ototoxicity by removing 4-hydroxynonenal (4-HNE) in the inner ears of female mice. Under cisplatin treatment, loss of Gsta4 results in more profound hearing loss in female mice compared to male mice. Cisplatin stimulates GSTA4 activity in the inner ear of female wild-type, but not male wild-type mice. In female Gsta4^-/- mice, cisplatin treatment results in increased levels of 4-HNE in cochlear neurons compared to male Gsta4^-/- mice. In CBA/CaJ mice, ovariectomy decreases mRNA expression of Gsta4, and the levels of GSTA4 protein in the inner ears. Thus, our findings suggest that GSTA4-dependent detoxification may play a role in estrogen-mediated neuroprotection.

논문정보

형식Research article
게재일2019년 09월 (BRIC 등록일 2019-10-08)
연구진국외 연구진
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