期刊
AUTOPHAGY
卷 17, 期 10, 页码 3221-3237出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2020.1851492
关键词
Autophagy; gefitinib; hepatotoxicity; PLK1
类别
资金
- National Natural Science Foundation for Distinguished Young Scholar of China [81625024]
- National Natural Science Foundation of China [81673522]
- Science Technology Plan Project of Zhejiang Province [2019C04010]
Liver dysfunction is a prominent dose-limiting toxicity of gefitinib, which activates autophagy and then apoptosis in hepatocytes. Autophagy is involved in gefitinib-induced hepatotoxicity, while PLK1 plays a crucial role in the autophagy-promoted apoptosis pathway. Pharmacological inhibition of PLK1 could be a promising therapeutic strategy to improve the safety of gefitinib-based cancer therapy.
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.
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