CASK Silence Overcomes Sorafenib Resistance of Hepatocellular Carcinoma Through Activating Apoptosis and Autophagic Cell Death

Abstract

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.

Drosophila CASK regulates brain size and neuronal morphogenesis, providing a genetic model of postnatal microcephaly suitable for drug discovery

“…First, an unbiased phenotypic screen does not require knowing which protein(s) or signaling pathways should be targeted to improve brain development and function in children with CASK -related disorders. Second, recently synthesized CASK inhibitors [ 133 ] may have benefit in treating gastrointestinal cancers [ 33 , 126 , 158 , 167 ] but would not help CASK -LOF neurodevelopmental disorders. In order to efficiently identify enhancers of CASK -dependent neurite-arbor morphogenesis, we developed a new method for preparation of primary neuronal cultures.…”

Negative effects of heat stress on ovarian tissue in female rabbit

“…RFC5 is a small subunit of replication factor and has been reported to involve in cell cycle progression ( 69 ). It is reported that downregulation of CASK could activate apoptosis and induce autophagic death through the JNK/c-Jun signaling pathway ( 70 ). HOXB6 has been reported to be associated with the occurrence of ovarian tumors ( 71 ).…”

The biological functions and pathological mechanisms of CASK in various diseases

“…CASK is significantly up-regulated in hepatocellular carcinoma (HCC), and HCC patients with a high expression of CASK have low overall survival rates. At the molecular level, the knockout of CASK activates the c-Jun N-terminal kinase (JNK) pathway, whereas treatment with the JNK inhibitor SP600125 or transient transfection with JNK-targeting siRNA can significantly reduce the knockout of CASK-mediated autophagic cell death [ 103 ].…”