Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Adv Sci (Weinh). 2023 Sep;10(25):e2300756. doi: 10.1002/advs.202300756. Epub 2023 Jul 13.
Liver metastasis is the most fatal event of colon cancer patients. Warburg effect has been long challenged by the fact of upregulated oxidative phosphorylation (OXPHOS), while its mechanism remains unclear. Here, metastasis-associated antigen 1 (MTA1) is identified as a newly identified adenosine triphosphate (ATP) synthase modulator by interacting with ATP synthase F1 subunit alpha (ATP5A), facilitates colon cancer liver metastasis by driving mitochondrial bioenergetic metabolism reprogramming, enhancing OXPHOS; therefore, modulating ATP synthase activity and downstream mTOR pathways. High-throughput screening of an anticancer drug shows MTA1 knockout increases the sensitivity of colon cancer to mitochondrial bioenergetic metabolism-targeted drugs and mTOR inhibitors. Inhibiting ATP5A enhances the sensitivity of liver-metastasized colon cancer to sirolimus in an MTA1-dependent manner. The therapeutic effects are verified in xenograft models and clinical cases. This research identifies a new modulator of mitochondrial bioenergetic reprogramming in cancer metastasis and reveals a new mechanism on upregulating mitochondrial OXPHOS as the reversal of Warburg effect in cancer metastasis is orchestrated.
肝转移是结肠癌患者最致命的事件。尽管氧化磷酸化（OXPHOS）的上调长期以来一直对沃伯格效应提出挑战，但其机制仍不清楚。在这里，转移相关抗原 1（MTA1）被鉴定为一种新的三磷酸腺苷（ATP）合成酶调节剂，通过与 ATP 合酶 F1 亚基α（ATP5A）相互作用，促进结肠癌肝转移，通过驱动线粒体生物能代谢重编程，增强 OXPHOS；因此，调节 ATP 合酶活性和下游 mTOR 途径。抗癌药物的高通量筛选表明，MTA1 敲除增加了结肠癌对线粒体生物能代谢靶向药物和 mTOR 抑制剂的敏感性。以 MTA1 依赖性方式抑制 ATP5A 增强了肝转移结肠癌对西罗莫司的敏感性。在异种移植模型和临床病例中验证了治疗效果。这项研究确定了癌症转移中线粒体生物能重编程的一个新调节剂，并揭示了上调线粒体 OXPHOS 的新机制，因为癌症转移中的沃伯格效应的逆转是由其协调的。
