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

Publisher: Elsevier Country of Publication: United States NLM ID: 100886622 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5586 (Electronic) Linking ISSN: 14765586 NLM ISO Abbreviation: Neoplasia Subsets: MEDLINE

Publication: 2014- : [Amsterdam] : Elsevier
Original Publication: New York, NY : Stockton Press, c1999-

Carcinoma, Hepatocellular*/pathology ; Carcinoma, Hepatocellular*/metabolism ; Carcinoma, Hepatocellular*/drug therapy ; Carcinoma, Hepatocellular*/genetics ; Liver Neoplasms*/pathology ; Liver Neoplasms*/metabolism ; Liver Neoplasms*/drug therapy ; Liver Neoplasms*/genetics ; Autophagy*/drug effects ; Mitochondria*/metabolism ; Mitochondria*/drug effects ; Endopeptidase Clp*/metabolism ; Endopeptidase Clp*/genetics ; Apoptosis*/drug effects; Humans ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Animals ; Mice ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/metabolism ; Antineoplastic Agents/pharmacology ; Xenograft Model Antitumor Assays ; Imidazoles/pharmacology ; Benzyl Compounds ; Heterocyclic Compounds, 3-Ring

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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier Inc.)

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Keywords: ClpP; HCC; ONC206; mitochondrial dysfunction; protective autophagy

EC 3.4.21.92 (ClpP protein, human)
EC 3.4.21.92 (Endopeptidase Clp)
0 (Reactive Oxygen Species)
0 (Antineoplastic Agents)
0 (Imidazoles)
0 (ONC206)
0 (Benzyl Compounds)
0 (Heterocyclic Compounds, 3-Ring)

Date Created: 20240630 Date Completed: 20240715 Latest Revision: 20240727

20240727

PMC11267062

10.1016/j.neo.2024.101015

38944913