Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment
Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment
复制标题
线粒体复合物 I 抑制剂通过同时酸化细胞内和细胞外环境来抑制肿瘤生长
DOI：
10.1016/j.isci.2021.103497
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发表时间：
2021
期刊：
影响因子：
5.8
通讯作者：
M. Shi
中科院分区：
文献类型：
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作者：
J. Yoshida;T. Ohishi;H. Abe;S. Ohba;H. Inoue;I. Usami;M. Amemiya;R. Oriez;C. Sakashita;S. Dan;M. Sugawara;T. Kawaguchi;J. Ueno;Y. Asano;A. Ikeda;M. Takamatsu;G. Amori;Y. Kondoh;K. Honda;H. Osada;T. Noda;T. Watanabe;T. Shimizu;M. Shi
破坏肿瘤微环境（TME）是一种很有前途的抗癌策略，但其对实体瘤的有效靶向仍然未知。在这里，我们研究了线粒体复合物I抑制剂intervenolin（ITV）的抗癌活性，该抑制剂独立于能量消耗调节TME。通过调节乳酸代谢，ITV诱导了细胞内和细胞外环境的伴随酸化，这通过蛋白磷酸酶-2A介导的去磷酸化（经由G蛋白偶联受体）协同抑制癌细胞中的S6 K1活性。其他复合物I抑制剂，包括二甲双胍和鱼藤酮也被发现通过能量消耗独立的方式发挥与ITV相同的作用。在小鼠和患者来源的异种移植模型中，发现ITV抑制肿瘤生长，并进一步证实了其作用模式。由于糖酵解癌细胞代谢，TME通常是酸性的，并且这种情况对复合物I抑制剂更敏感。因此，我们已经证明了实体瘤的潜在治疗策略。
The disruption of the tumor microenvironment (TME) is a promising anti-cancer strategy, but its effective targeting for solid tumors remains unknown. Here, we investigated the anti-cancer activity of the mitochondrial complex I inhibitor intervenolin (ITV), which modulates the TME independent of energy depletion. By modulating lactate metabolism, ITV induced the concomitant acidification of the intra- and extracellular environment, which synergistically suppressed S6K1 activity in cancer cells through protein phosphatase-2A-mediated dephosphorylation via G-protein-coupled receptor(s). Other complex I inhibitors including metformin and rotenone were also found to exert the same effect through an energy depletion-independent manner as ITV. In mouse and patient-derived xenograft models, ITV was found to suppress tumor growth and its mode of action was further confirmed. The TME is usually acidic owing to glycolytic cancer cell metabolism, and this condition is more susceptible to complex I inhibitors. Thus, we have demonstrated a potential treatment strategy for solid tumors.