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

IF 4.8 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology
Jiahao Cao , Fei Cao , Chuanzheng Wang , Zhen Jiao , Yuting You , Xiaomin Wang , Wenxiu Zhao
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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.

Abstract Image

以ClpP为靶点的ONC206可诱导肝癌细胞线粒体功能障碍和保护性自噬。
肝细胞癌(HCC)是最常见的肝癌,约占所有病例的 90%。ONC201是亚胺培酮药物家族中的一员,在恶性小儿中枢神经系统肿瘤(弥漫中线胶质瘤[DMG])和血液系统恶性肿瘤中显示出良好的治疗潜力和安全性。ONC206 是 ONC201 的强效类似物。然而,ONC206在HCC中的潜力和作用机制仍有待阐明。我们发现,ONC206 通过抑制细胞增殖和诱导细胞凋亡来阻碍 HCC 的生长。此外,ONC206还能诱导细胞保护性自噬,而阻断自噬能增强ONC206的促凋亡作用。此外,ONC206 还能诱导线粒体肿胀,降低线粒体膜电位(MMP),并导致 HCC 细胞线粒体 ROS 的积累,最终导致线粒体功能障碍。HCC患者样本中的酪蛋白溶解蛋白酶蛋白水解亚基(ClpP)水平明显升高,而ClpP是ONC206诱导线粒体功能障碍和激活保护性自噬的介质。总之,我们的研究结果首次揭示了ONC206通过ClpP在HCC细胞中发挥抗HCC作用并诱导保护性自噬的机制。
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来源期刊
Neoplasia
Neoplasia 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
82
审稿时长
26 days
期刊介绍: Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.
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