GSTA4 mediates reduction of cisplatin ototoxicity in female mice

Hyo Jin Park; Mi Jung Kim; Christina Rothenberger; Ashok Kumar; Edith M. Sampson; Dalian Ding; Chul Han; Karessa White; Kevin Boyd; Senthilvelan Manohar; Yong Hwan Kim; Maria S. Ticsa; Aaron S. Gomez; Isabela Caicedo; Upal Bose; Paul J. Linser; Takuya Miyakawa; Masaru Tanokura; Thomas C. Foster; Richard Salvi; Shinichi Someya

doi:10.1038/s41467-019-12073-0

GSTA4 mediates reduction of cisplatin ototoxicity in female mice

Hyo Jin Park
, Mi Jung Kim
, Christina Rothenberger
, Ashok Kumar
, Edith M. Sampson
, Dalian Ding
, Chul Han
, Karessa White
, Kevin Boyd
, Senthilvelan Manohar
, Yong Hwan Kim
, Maria S. Ticsa
, Aaron S. Gomez
, Isabela Caicedo
, Upal Bose
, Paul J. Linser
, Takuya Miyakawa
, Masaru Tanokura
, Thomas C. Foster
, Richard Salvi

Shinichi Someya

Communicative Disorders and Sciences

University of Florida
St. Joseph's Hospital and Medical Center, Phoenix
The University of Tokyo

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

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.

Original language	English
Article number	4150
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12073-0
State	Published - Dec 1 2019

Access to Document

10.1038/s41467-019-12073-0

Cite this

Park, H. J., Kim, M. J., Rothenberger, C., Kumar, A., Sampson, E. M., Ding, D., Han, C., White, K., Boyd, K., Manohar, S., Kim, Y. H., Ticsa, M. S., Gomez, A. S., Caicedo, I., Bose, U., Linser, P. J., Miyakawa, T., Tanokura, M., Foster, T. C., ... Someya, S. (2019). GSTA4 mediates reduction of cisplatin ototoxicity in female mice. Nature Communications, 10(1), Article 4150. https://doi.org/10.1038/s41467-019-12073-0

@article{7bbfd3da2a6945288a1d2b2d1bc211ac,

title = "GSTA4 mediates reduction of cisplatin ototoxicity in female mice",

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.",

author = "Park, \{Hyo Jin\} and Kim, \{Mi Jung\} and Christina Rothenberger and Ashok Kumar and Sampson, \{Edith M.\} and Dalian Ding and Chul Han and Karessa White and Kevin Boyd and Senthilvelan Manohar and Kim, \{Yong Hwan\} and Ticsa, \{Maria S.\} and Gomez, \{Aaron S.\} and Isabela Caicedo and Upal Bose and Linser, \{Paul J.\} and Takuya Miyakawa and Masaru Tanokura and Foster, \{Thomas C.\} and Richard Salvi and Shinichi Someya",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-12073-0",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Park, HJ, Kim, MJ, Rothenberger, C, Kumar, A, Sampson, EM, Ding, D, Han, C, White, K, Boyd, K, Manohar, S, Kim, YH, Ticsa, MS, Gomez, AS, Caicedo, I, Bose, U, Linser, PJ, Miyakawa, T, Tanokura, M, Foster, TC, Salvi, R & Someya, S 2019, 'GSTA4 mediates reduction of cisplatin ototoxicity in female mice', Nature Communications, vol. 10, no. 1, 4150. https://doi.org/10.1038/s41467-019-12073-0

TY - JOUR

T1 - GSTA4 mediates reduction of cisplatin ototoxicity in female mice

AU - Park, Hyo Jin

AU - Kim, Mi Jung

AU - Rothenberger, Christina

AU - Kumar, Ashok

AU - Sampson, Edith M.

AU - Ding, Dalian

AU - Han, Chul

AU - White, Karessa

AU - Boyd, Kevin

AU - Manohar, Senthilvelan

AU - Kim, Yong Hwan

AU - Ticsa, Maria S.

AU - Gomez, Aaron S.

AU - Caicedo, Isabela

AU - Bose, Upal

AU - Linser, Paul J.

AU - Miyakawa, Takuya

AU - Tanokura, Masaru

AU - Foster, Thomas C.

AU - Salvi, Richard

AU - Someya, Shinichi

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85072150617

U2 - 10.1038/s41467-019-12073-0

DO - 10.1038/s41467-019-12073-0

M3 - Article

C2 - 31515474

AN - SCOPUS:85072150617

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4150

ER -

GSTA4 mediates reduction of cisplatin ototoxicity in female mice

Abstract

Access to Document

Other files and links

Fingerprint

Cite this