Zhang Qiongsi, Peng Jia, Li Zhiguo, Rao Xiongjian, Allison Derek B, Qiao Qi, Zhang Zhuangzhuang, Kong Yifan, Zhang Yanquan, Wang Ruixin, Liu Jinghui, Wang Xinyi, Li Chaohao, Mao Fengyi, Shao Qing, Gao Tianyan, Liu Xiaoqi
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA.
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA; Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
J Biol Chem. 2025 Jul;301(7):110406. doi: 10.1016/j.jbc.2025.110406. Epub 2025 Jun 20.
Hexavalent chromium (Cr(VI)) is a class I environmental carcinogen that induces lung epithelial cell transformation and promotes lung cancer progression by altering cell cycle regulation and cellular energy metabolism. In this study, we investigated the role of polo-like kinase 1 (PLK1) in Cr(VI)-transformed (CrT) bronchial epithelial cells (BEAS-2B) and found that PLK1 expression was significantly upregulated in these cells, leading to impaired mitochondrial function and enhanced mitophagy, which in turn stimulated cell proliferation both in vitro and in vivo. Mechanistically, we demonstrated that PLK1 directly phosphorylates the pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) at Thr57, leading to its destabilization and disruption of pyruvate dehydrogenase complex (PDHc) integrity. This modification inhibits oxidative phosphorylation (OXPHOS) and induces mitochondrial dysfunction. Furthermore, mitochondrial dysfunction triggers mitophagy and accelerates PDHA1 degradation, establishing a positive feedback loop that amplifies mitochondrial impairment and mitophagy, ultimately promoting cancer cell proliferation. These findings underscore the pivotal role of PLK1 in Cr(VI)-associated cancer progression and offer new insights into potential therapeutic targets to inhibit Cr(VI)-induced tumorigenesis.
六价铬（Cr(VI)）是一种I类环境致癌物，可诱导肺上皮细胞转化，并通过改变细胞周期调控和细胞能量代谢促进肺癌进展。在本研究中，我们调查了polo样激酶1（PLK1）在Cr(VI)转化的（CrT）支气管上皮细胞（BEAS-2B）中的作用，发现这些细胞中PLK1表达显著上调，导致线粒体功能受损和线粒体自噬增强，进而在体外和体内刺激细胞增殖。机制上，我们证明PLK1直接在Thr57位点磷酸化丙酮酸脱氢酶E1亚基α1（PDHA1），导致其不稳定并破坏丙酮酸脱氢酶复合体（PDHc）的完整性。这种修饰抑制氧化磷酸化（OXPHOS）并诱导线粒体功能障碍。此外，线粒体功能障碍触发线粒体自噬并加速PDHA1降解，建立一个正反馈回路，放大线粒体损伤和线粒体自噬，最终促进癌细胞增殖。这些发现强调了PLK1在Cr(VI)相关癌症进展中的关键作用，并为抑制Cr(VI)诱导的肿瘤发生的潜在治疗靶点提供了新见解。
