CASK Silence Overcomes Sorafenib Resistance of Hepatocellular Carcinoma Through Activating Apoptosis and Autophagic Cell Death.
CASK Silence Overcomes Sorafenib Resistance of Hepatocellular Carcinoma Through Activating Apoptosis and Autophagic Cell Death.
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CASK沉默通过激活细胞凋亡和自噬细胞死亡克服肝细胞癌的索拉非尼耐药性
DOI：
10.3389/fonc.2021.681683
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发表时间：
2021
影响因子：
4.7
通讯作者：
Lou W
中科院分区：
文献类型：
--
作者：
Ding B;Bao C;Jin L;Xu L;Fan W;Lou W
肝细胞癌（HCC）患者通常因耐药而无法治疗，包括索拉非尼。本研究通过细胞计数kit-8法、集落形成实验、流式细胞术、透射电镜、免疫荧光共聚焦激光显微镜、异种移植瘤实验和免疫组化染色等方法，采用功能获得或功能丧失策略，研究CASK对肝癌细胞的作用。目前的研究结果表明，CASK表达与索拉非尼耐药和肝癌预后不良呈正相关。此外，抑制CASK部分通过促进细胞凋亡和自噬来增加索拉非尼的作用，而CASK过表达则表现出相反的作用。此外，当索拉非尼处理时，使用泛半胱天冬酶抑制剂Z-VAD-FMK抑制凋亡和使用自噬抑制剂3-甲基腺嘌呤（3-MA）或LC3B的小干扰RNA（siRNA）抑制自噬都显著逆转CASK敲除诱导的效应，表明凋亡和自噬都参与了CASK介导的上述功能，自噬在本研究中起促死亡作用。有趣的是，在体内观察到类似的结果。在分子水平上，CASK基因敲除激活了c-Jun N-末端激酶（JNK）通路，JNK抑制剂SP600125或靶向JNK的siRNA瞬时转染显著减弱了CASK基因敲除介导的自噬性细胞死亡。总之，所有这些结果共同表明，CASK可能是一个有前途的生物标志物和肝癌患者的潜在治疗靶点。
Hepatocellular carcinoma (HCC) patients usually fail to be treated because of drug resistance, including sorafenib. In this study, the effects of CASK in HCC were investigated using gain- or loss-of-function strategies by performing cell counting kit-8 assay, colony formation assay, flow cytometry, transmission electron microscopy, immunofluorescent confocal laser microscopy, tumor xenograft experiment and immunohistochemistry staining. The current results suggested that CASK expression was positively associated with sorafenib resistance and poor prognosis of HCC. Moreover, inhibition of CASK increased the role of sorafenib partially by promoting apoptosis and autophagy, while CASK overexpression presented the opposite effects. Besides, when treatment with sorafenib, inhibition of apoptosis using the pan-caspase inhibitor Z-VAD-FMK and inhibition of autophagy using autophagy inhibitor 3-Methyladenine (3-MA) or small interfering RNA (siRNA) of LC3B all significantly reversed CASK knockout-induced effects, suggesting that both apoptosis and autophagy were involved in CASK-mediated above functions and autophagy played a pro-death role in this research. Intriguingly, similar results were observed in vivo. In molecular level, CASK knockout activated the c-Jun N-terminal kinase (JNK) pathway, and treatment with JNK inhibitor SP600125 or transiently transfected with siRNA targeting JNK significantly attenuated CASK knockout-mediated autophagic cell death. Collectively, all these results together indicated that CASK might be a promising biomarker and a potential therapeutic target for HCC patients.
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