PLK1 (polo like kinase 1)-dependent autophagy facilitates gefitinib-induced hepatotoxicity by degrading COX6A1 (cytochrome c oxidase subunit 6A1).
PLK1 (polo like kinase 1)-dependent autophagy facilitates gefitinib-induced hepatotoxicity by degrading COX6A1 (cytochrome c oxidase subunit 6A1).
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PLK1（polo样激酶1）依赖性自噬通过降解COX6A1（细胞色素c氧化酶亚基6A1）促进吉非替尼诱导的肝毒性
DOI：
10.1080/15548627.2020.1851492
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发表时间：
2021-10
期刊：
影响因子：
13.3
通讯作者：
He Q
中科院分区：
文献类型：
--
作者：
Luo P;Yan H;Du J;Chen X;Shao J;Zhang Y;Xu Z;Jin Y;Lin N;Yang B;He Q
摘要肝功能障碍是表皮生长因子受体酪氨酸激酶抑制剂(TKI)吉非替尼治疗EGFR突变阳性非小细胞肺癌(NSCLC)的显著剂量限制性毒性。我们的目的是阐明吉非替尼引起肝毒性的机制，并提供潜在有效的干预策略。我们发现吉非替尼可以顺次激活肝细胞的巨噬/自噬和凋亡。抑制自噬可减轻吉非替尼诱导的细胞凋亡，而抑制细胞凋亡不能减轻吉非替尼诱导的自噬。此外，肝脏特异性ATG7+/−杂合子小鼠的肝脏损伤没有载体小鼠严重，这表明自噬参与了吉非替尼促进的肝脏毒性。在机制上，吉非替尼选择性地降解自噬-溶酶体途径中重要的抗凋亡因子COX6A1(细胞色素C氧化酶6A1)。吉非替尼诱导的COX6A1的降低损害了线粒体呼吸链复合体IV(RCC IV)的功能，而RCC IV又激活了细胞凋亡，从而导致肝损伤。值得注意的是，这种自噬促进的细胞凋亡依赖于PLK1(Polo Like Kinase1)。AAV8介导的Plk1基因敲除和PLK1抑制剂BI-2536均可通过抑制COX6A1蛋白的自噬降解而减轻Gefitinib诱导的体内肝毒性。此外，抑制PLK1不影响吉非替尼的抗癌活性。总之，我们的研究结果揭示了吉非替尼-肝毒性途径，其中自噬通过降解COX6A1促进细胞凋亡，并强调了PLK1的药理抑制是提高基于吉非替尼的癌症治疗安全性的一种有吸引力的治疗方法。缩写：3-MA：3-甲基腺嘌呤；AAV8：腺相关病毒血清8型；ATG5：自噬相关5；ATG7：自噬相关7；B2M：β-2-微球蛋白；CCCP：乙酰氰基间氯苯肼；CHX：环己亚胺；COX6A1：细胞色素c氧化酶亚基6A1；c-PARP：裂解多聚(ADP-核糖)聚合酶；CQ：氯喹；GOT1/AST：谷草转氨酶1，可溶性；GPT/ALT：谷丙转氨酶，可溶性；HBSS：平衡盐溶液；H&E：苏木精和伊红；MAP1LC3/3：微管相关蛋白1轻链；PLK1：谷草转氨酶1，可溶性；GPT/ALT：谷丙转氨酶：汉克斯平衡盐溶液；H&E：苏木精和伊红；MAP1LC3/3：微管相关蛋白1轻链；PLK1：谷草转氨酶1，可溶性；GPT/ALT：谷丙转氨酶，可溶性；HBSS：汉氏平衡盐溶液；H&E：苏木精和伊红；MAP1LC3/3：微管相关蛋白1轻链；PLK1：谷草转氨酶1，可溶性；GPT/ALT：谷丙转氨酶，可溶性；HBSS：汉氏平衡盐溶液；H&E：苏木精和伊红；MAP1LC3/3：微管相关蛋白1轻链；PLK1：谷草转氨酶1，可溶；GPT/ALT：谷丙转氨酶1，可溶性；HBSS：汉氏平衡盐溶液；H&E：苏木精和伊红；MAP1LC3/3：微管相关蛋白1轻链；PLK1：谷草转氨RCC IV：呼吸链复合体IV；ROS：活性氧物种；TUBB8：微管蛋白β8类
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
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影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
影响因子：
13.3
作者：
Chen, Lei-Lei;Wang, Yong-Bo;Xue, Yu
通讯作者：
Xue, Yu
影响因子：
2.9
作者：
Chen X;Pan Y;Zhang S;Chen D;Yang S;Li X;Ma S
通讯作者：
Ma S
影响因子：
51.1
作者：
Mitsudomi, Tetsuya;Morita, Satoshi;Fukuoka, Masahiro
通讯作者：
Fukuoka, Masahiro
DOI：
10.1083/jcb.201603039
发表时间：
2016-08-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
McWilliams TG;Prescott AR;Allen GF;Tamjar J;Munson MJ;Thomson C;Muqit MM;Ganley IG
通讯作者：
Ganley IG