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PLK1 (polo like kinase 1)-dependent autophagy facilitates gefitinib-induced hepatotoxicity by degrading COX6A1 (cytochrome c oxidase subunit 6A1).
Luo, Peihua; Yan, Hao; Du, Jiangxia; Chen, Xueqin; Shao, Jinjin; Zhang, Ying; Xu, Zhifei; Jin, Ying; Lin, Nengming; Yang, Bo; He, Qiaojun.
Afiliação
  • Luo P; Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, China.
  • Yan H; Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, China.
  • Du J; Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, China.
  • Chen X; Department of Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People´s Hospital, Zhejiang University School of Medicine , Hangzhou, China.
  • Shao J; Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, China.
  • Zhang Y; Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, China.
  • Xu Z; Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, China.
  • Jin Y; Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, China.
  • Lin N; Laboratory of Clinical Pharmacology, Affiliated Hangzhou First People´s Hospital, Zhejiang University School of Medicine , Hangzhou, China.
  • Yang B; Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, China.
  • He Q; Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, China.
Autophagy ; : 1-17, 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33315519
ABSTRACT
Liver dysfunction is an outstanding dose-limiting toxicity of gefitinib, an EGFR (epidermal growth factor receptor)-tyrosine kinase inhibitor (TKI), in the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to elucidate the mechanisms underlying gefitinib-induced hepatotoxicity, and provide potentially effective intervention strategy. We discovered that gefitinib could sequentially activate macroautophagy/autophagy and apoptosis in hepatocytes. The inhibition of autophagy alleviated gefitinib-induced apoptosis, whereas the suppression of apoptosis failed to lessen gefitinib-induced autophagy. Moreover, liver-specific Atg7 +/- heterozygous mice showed less severe liver injury than vehicle, suggesting that autophagy is involved in the gefitinib-promoted hepatotoxicity. Mechanistically, gefitinib selectively degrades the important anti-apoptosis factor COX6A1 (cytochrome c oxidase subunit 6A1) in the autophagy-lysosome pathway. The gefitinib-induced COX6A1 reduction impairs mitochondrial respiratory chain complex IV (RCC IV) function, which in turn activates apoptosis, hence causing liver injury. Notably, this autophagy-promoted apoptosis is dependent on PLK1 (polo like kinase 1). Both AAV8-mediated Plk1 knockdown and PLK1 inhibitor BI-2536 could mitigate the gefitinib-induced hepatotoxicity in vivo by abrogating the autophagic degradation of the COX6A1 protein. In addition, PLK1 inhibition could not compromise the anti-cancer activity of gefitinib. In conclusion, our findings reveal the gefitinib-hepatotoxicity pathway, wherein autophagy promotes apoptosis through COX6A1 degradation, and highlight pharmacological inhibition of PLK1 as an attractive therapeutic approach toward improving the safety of gefitinib-based cancer therapy. Abbreviations 3-MA 3-methyladenine; AAV8 adeno-associated virus serotype 8; ATG5 autophagy related 5; ATG7 autophagy related 7; B2M beta-2-microglobulin; CCCP carbonyl cyanide m-chlorophenylhydrazone; CHX cycloheximide; COX6A1 cytochrome c oxidase subunit 6A1; c-PARP cleaved poly(ADP-ribose) polymerase; CQ chloroquine; GOT1/AST glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT glutamic pyruvic transaminase, soluble; HBSS Hanks´ balanced salt solution; H&E hematoxylin and eosin; MAP1LC3/LC3 microtubule associated proteins 1 light chain 3; PLK1 polo like kinase 1; RCC IV respiratory chain complex IV; ROS reactive oxygen species; TUBB8 tubulin beta 8 class VIII.
Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Idioma: Inglês Revista: Autophagy Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: China

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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Idioma: Inglês Revista: Autophagy Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: China