Abstract：
Mitochondrial Pyruvate Carrier 1 (MPC1) is localized on mitochondrial outer membrane to mediate the transport of pyruvate from cytosol to mitochondria. It is also well known to act as a tumor suppressor. Hexavalent chromium (Cr (VI)) contamination poses a global challenge due to its high toxicity and carcinogenesis. This research was intended to probe the potential mechanism of MPC1 in the effect of Cr (VI)-induced carcinogenesis. First, Cr (VI)-treatments decreased the expression of MPC1 in vitro and in vivo. Overexpression of MPC1 inhibited Cr (VI)-induced glycolysis and migration in A549 cells. Then, high mobility group A2 (HMGA2) protein strongly suppressed the transcription of MPC1 by binding to its promoter, and HMGA2/MPC1 axis played an important role in oxidative phosphorylation (OXPHOS), glycolysis and cell migration. Furthermore, endoplasmic reticulum (ER) stress made a great effect on the interaction between HMGA2 and MPC1. Finally, the mammalian target of the rapamycin (mTOR) was determined to mediate MPC1-regulated OXPHOS, aerobic glycolysis and cell migration. Collectively, our data revealed a novel HMGA2/MPC-1/mTOR signaling pathway to promote cell growth via facilitating the metabolism reprogramming from OXPHOS to aerobic glycolysis, which might be a potential therapy for cancers.
摘要：
线粒体丙酮酸盐载体1(MPC1)定位于线粒体外膜上以介导丙酮酸盐从胞质溶胶向线粒体的转运。它作为肿瘤抑制因子也是众所周知的。六价铬（Cr（VI））污染由于其高毒性和致癌作用而提出了全球性挑战。本研究旨在探讨MPC1在Cr（VI）诱导致癌作用中的潜在机制。首先,Cr(VI)处理在体外和体内降低了MPC1的表达。MPC1过表达抑制Cr(VI)诱导的A549细胞糖酵解和迁移。然后，高迁移率族A2（HMGA2）蛋白通过与其启动子结合强烈抑制MPC1的转录，HMGA2/MPC1轴在氧化磷酸化（OXPHOS）中发挥了重要作用，糖酵解和细胞迁移。此外，内质网(ER)应激对HMGA2和MPC1之间的相互作用有很大的影响。最后,确定哺乳动物雷帕霉素靶蛋白（mTOR）介导MPC1调节的OXPHOS，有氧糖酵解和细胞迁移。总的来说，我们的数据揭示了一种新的HMGA2/MPC-1/mTOR信号通路，通过促进从OXPHOS到有氧糖酵解的代谢重编程来促进细胞生长，这可能是癌症的潜在治疗方法。
