2. Academic Validation
  3. ONC206 targeting ClpP induces mitochondrial dysfunction and protective autophagy in hepatocellular carcinoma cells

ONC206 targeting ClpP induces mitochondrial dysfunction and protective autophagy in hepatocellular carcinoma cells

  • Neoplasia. 2024 Sep:55:101015. doi: 10.1016/j.neo.2024.101015.
Jiahao Cao 1,  Fei Cao 2,  Chuanzheng Wang 2,  Zhen Jiao 2,  Yuting You 2,  Xiaomin Wang 3,  Wenxiu Zhao 4
Affiliations

Affiliations

  • 1 Xiamen Key Laboratory of Translational Medical of Digestive System Tumor, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361004, PR China; Department of Thyroid Head and Neck Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314099, PR China.
  • 2 Xiamen Key Laboratory of Translational Medical of Digestive System Tumor, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361004, PR China.
  • 3 Xiamen Key Laboratory of Translational Medical of Digestive System Tumor, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361004, PR China. Electronic address: wxm2203@xmu.edu.cn.
  • 4 Xiamen Key Laboratory of Translational Medical of Digestive System Tumor, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361004, PR China. Electronic address: wxzhao@xmu.edu.cn.
PMID: 38944913 DOI: 10.1016/j.neo.2024.101015
Abstract

Hepatocellular carcinoma (HCC) is the most common form of liver Cancer, accounting for approximately 90 % of all cases. ONC201, a member of the imipridone drug family, has shown promising therapeutic potential and a good safety profile in both malignant pediatric central nervous system tumors (diffuse midline glioma [DMG]) and hematologic malignancies. ONC206 is a more potent analog of ONC201. However, the ONC206 potential and mechanism of action in HCC remain to be elucidated. We found that ONC206 hindered HCC growth by suppressing cell proliferation and inducing Apoptosis. Moreover, ONC206 induced cytoprotective Autophagy, and blocking Autophagy enhanced the proapoptotic effect of ONC206. Additionally, ONC206 induced mitochondrial swelling, reduced the mitochondrial membrane potential (MMP), and led to the accumulation of mitochondrial ROS in HCC cells, ultimately resulting in mitochondrial dysfunction. The HCC patient samples exhibited notably elevated levels of caseinolytic Protease proteolytic subunit (ClpP), which serves as a mediator of ONC206-induced mitochondrial dysfunction and the activation of protective Autophagy. knockdown of ClpP reversed the cytotoxic effects of ONC206 on HCC cells. In summary, our results provide the first insight into the mechanism by which ONC206 exerts its anti-HCC effects and induces protective Autophagy in HCC cells through ClpP.

Keywords

ClpP; HCC; ONC206; mitochondrial dysfunction; protective autophagy.

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