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Updated: Oct 29, 2025

An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
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CASK Silence Overcomes Sorafenib Resistance of Hepatocellular Carcinoma Through Activating Apoptosis and Autophagic

Bisha Ding1,2, Chang Bao2, Luqi Jin3

  • 1Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Frontiers in Oncology
|July 12, 2021
PubMed

Insights

Calcium/calmodulin-dependent serine protein kinase (CASK) promotes sorafenib resistance in hepatocellular carcinoma (HCC). Inhibiting CASK enhances sorafenib efficacy by promoting apoptosis and autophagy, suggesting CASK as a therapeutic target for HCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Resistance Research

Background:

  • Hepatocellular carcinoma (HCC) treatment is often hindered by drug resistance, particularly to sorafenib.
  • The role of Calcium/calmodulin-dependent serine protein kinase (CASK) in HCC progression and drug resistance remains largely unexplored.

Purpose of the Study:

  • To investigate the functional role of CASK in hepatocellular carcinoma (HCC) and its association with sorafenib resistance.
  • To elucidate the molecular mechanisms underlying CASK's influence on HCC cell death pathways and therapeutic response.

Main Methods:

  • Utilized gain- and loss-of-function strategies to manipulate CASK expression in HCC cells.
  • Employed cell counting kit-8 assay, colony formation assay, flow cytometry, transmission electron microscopy, immunofluorescence, xenograft experiments, and immunohistochemistry.
  • Investigated the involvement of apoptosis and autophagy pathways, including the c-Jun N-terminal kinase (JNK) signaling.

Main Results:

  • CASK expression positively correlated with sorafenib resistance and poor prognosis in HCC patients.
  • CASK inhibition enhanced sorafenib efficacy by promoting apoptosis and autophagy, while CASK overexpression had opposite effects.
  • Both apoptosis and autophagy were implicated in CASK-mediated effects, with autophagy playing a pro-death role, and CASK knockout activated the JNK pathway.

Conclusions:

  • CASK plays a significant role in promoting sorafenib resistance and influencing cell death pathways in HCC.
  • Targeting CASK, potentially through modulating apoptosis and autophagy via the JNK pathway, could overcome sorafenib resistance.
  • CASK represents a promising biomarker and a potential therapeutic target for improving HCC patient outcomes.
Keywords:
CASKHCCapoptosisautophagysorafenib resistance

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