Cisplatin-Mediated Upregulation of APE2 Binding to MYH9 Provokes Mitochondrial Fragmentation and Acute Kidney Injury

Yi Hu, Chun Yang, Tania Amorim, Mohsin Maqbool, Jenny Lin, Chen Li, Chuanfeng Fang, Li Xue, Ariel Kwart, Hua Fang, Mei Yin, Allison J. Janocha, Daisuke Tsuchimoto, Yusaku Nakabeppu, Xiaofeng Jiang, Alex Mejia-Garcia, Faiz Anwer, Jack Khouri, Xin Qi, Qing Y. ZhengJennifer S. Yu, Shan Yan, Thomas LaFramboise, Kenneth C. Anderson, Leal C. Herlitz, Nikhil C. Munshi, Jianhong Lin, Jianjun Zhao

研究成果: Contribution to journalArticle査読

抄録

Cisplatin chemotherapy is standard care for many cancers but is toxic to the kidneys. How this toxicity occurs is uncertain. In this study, we identified apurinic/apyrimidinic endonuclease 2 (APE2) as a critical molecule upregulated in the proximal tubule cells (PTC) following cisplatin-induced nuclear DNA and mitochondrial DNA damage in cisplatin-treated C57B6J mice. The APE2 transgenic mouse phenotype recapitulated the pathophysiological features of C-AKI (acute kidney injury, AKI) in the absence of cisplatin treatment. APE2 pulldown-MS analysis revealed that APE2 binds myosin heavy-Chain 9 (MYH9) protein in mitochondria after cisplatin treatment. Human MYH9-related disorder is caused by mutations in MYH9 that eventually lead to nephritis, macrothrombocytopenia, and deafness, a constellation of symptoms similar to the toxicity profile of cisplatin. Moreover, cisplatin-induced C-AKI was attenuated in APE2-knockout mice. Taken together, these findings suggest that cisplatin promotes AKI development by upregulating APE2, which leads to subsequent MYH9 dysfunction in PTC mitochondria due to an unrelated role of APE2 in DNA damage repair. This postulated mechanism and the availability of an engineered transgenic mouse model based on the mechanism of C-AKI provides an opportunity to identify novel targets for prophylactic treatment of this serious disease.

本文言語英語
ページ(範囲)713-723
ページ数11
ジャーナルCancer Research
81
3
DOI
出版ステータス出版済み - 2 1 2021

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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