Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, 325000, Zhejiang, China.
Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Arch Biochem Biophys. 2024 Aug;758:110047. doi: 10.1016/j.abb.2024.110047. Epub 2024 Jun 4.
Antioxidants exert a paradoxical influence on cancer prevention. The latest explanation for this paradox is the different target sites of antioxidants. However, it remains unclear how mitochondria-targeted antioxidants trigger specific p53-dependent pathways in malignant transformation models. Our study revealed that overexpression of mitochondria-targeted catalase (mCAT) instigated such malignant transformation via mouse double minute 2 homolog (MDM2) -mediated p53 degradation. In mouse epithelial JB6 Cl41 cells, the stable expression of mCAT resulted in MDM2-mediated p53 degradation, unlike in catalase-overexpressed Cl41 cells. Further, we demonstrated that mCAT overexpression upregulated ubiquitin-specific protease 28 (USP28) expression, which in turn stabilized c-Jun protein levels. This alteration initiated the activation of the miR-200b promoter transcription activity and a subsequent increase in miR-200b expression. Furthermore, elevated miR-200b levels then promoted its binding to the 3'-untranslated region of protein phosphatase 2A catalytic subunit (PP2A-C) α-isoform mRNA, consequently resulting in PP2A-C protein downregulation. This cascade of events ultimately contributed to increased MDM2 phosphorylation and p53 protein degradation. Thus, the mCAT overexpression triggers MDM2/p53-dependent malignant transformation through USP28/miR-200b/PP2A-Cα pathway, which may provide a new information for understanding mitochondria-targeted antioxidants facilitate the progression to the tumorigenic state.
抗氧化剂对癌症预防有矛盾的影响。对于这种矛盾的最新解释是抗氧化剂的不同靶位。然而，线粒体靶向抗氧化剂如何在恶性转化模型中触发特定的 p53 依赖性途径尚不清楚。我们的研究表明，过表达线粒体靶向过氧化氢酶 (mCAT) 通过鼠双微体 2 同源物 (MDM2) 介导的 p53 降解引发这种恶性转化。在小鼠上皮 JB6 Cl41 细胞中，mCAT 的稳定表达导致 MDM2 介导的 p53 降解，而不是在过氧化氢酶过表达的 Cl41 细胞中。此外，我们证明 mCAT 过表达上调了泛素特异性蛋白酶 28 (USP28) 的表达，进而稳定了 c-Jun 蛋白水平。这种改变启动了 miR-200b 启动子转录活性的增加，随后 miR-200b 的表达增加。此外，升高的 miR-200b 水平促进了其与蛋白磷酸酶 2A 催化亚基 (PP2A-C) α-同工型 mRNA 的 3'-非翻译区结合，从而导致 PP2A-C 蛋白下调。这一连串事件最终导致 MDM2 磷酸化和 p53 蛋白降解增加。因此，mCAT 过表达通过 USP28/miR-200b/PP2A-Cα 途径触发 MDM2/p53 依赖性恶性转化，这可能为理解线粒体靶向抗氧化剂促进肿瘤发生状态提供新信息。
