Cardiovascular Institute and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.
J Clin Invest. 2018 Oct 1;128(10):4543-4556. doi: 10.1172/JCI120912. Epub 2018 Sep 17.
The M2 isoform of pyruvate kinase (PKM2) is highly expressed in most cancer cells, and has been studied extensively as a driver of oncogenic metabolism. In contrast, the role of PKM2 in nontransformed cells is little studied, and nearly nothing is known of its role, if any, in quiescent cells. We show here that endothelial cells express PKM2 almost exclusively over PKM1. In proliferating endothelial cells, PKM2 is required to suppress p53 and maintain cell cycle progression. In sharp contrast, PKM2 has a strikingly different role in quiescent endothelial cells, where inhibition of PKM2 leads to degeneration of tight junctions and barrier function. Mechanistically, PKM2 regulates barrier function independently of its canonical activity as a pyruvate kinase. Instead, PKM2 suppresses NF-kB and its downstream target, the vascular permeability factor angiopoietin 2. As a consequence, loss of endothelial cell PKM2 in vivo predisposes mice to VEGF-induced vascular leak, and to severe bacteremia and death in response to sepsis. Together, these data demonstrate new roles of PKM2 in quiescent cells, and highlight the need for caution in developing cancer therapies that target PKM2.
丙酮酸激酶 M2 同工酶（PKM2）在大多数癌细胞中高度表达，作为致癌代谢的驱动因素，已经得到了广泛研究。相比之下，PKM2 在未转化细胞中的作用研究甚少，对于其在静止细胞中的作用，如果有的话，几乎一无所知。我们在这里表明内皮细胞表达的 PKM2 几乎完全超过 PKM1。在增殖的内皮细胞中，PKM2 被需要来抑制 p53 并维持细胞周期进程。与此形成鲜明对比的是，PKM2 在静止的内皮细胞中具有截然不同的作用，其中 PKM2 的抑制导致紧密连接和屏障功能的退化。从机制上讲，PKM2 调节屏障功能独立于其作为丙酮酸激酶的典型活性。相反，PKM2 抑制 NF-kB 及其下游靶标血管通透性因子血管生成素 2。因此，内皮细胞中 PKM2 的缺失使小鼠易发生 VEGF 诱导的血管渗漏，并在败血症时易发生严重的菌血症和死亡。总的来说，这些数据表明 PKM2 在静止细胞中的新作用，并强调在开发针对 PKM2 的癌症治疗方法时需要谨慎。
