High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
University of Science and Technology of China, Hefei, 230036, China.
Acta Pharmacol Sin. 2021 Apr;42(4):633-640. doi: 10.1038/s41401-020-0465-8. Epub 2020 Jul 31.
Inhibition of glycolysis process has been an attractive approach for cancer treatment due to the evidence that tumor cells are more dependent on glycolysis rather than oxidative phosphorylation pathway. Preliminary evidence shows that inhibition of phosphoglycerate kinase 1 (PGK1) kinase activity would reverse the Warburg effect and make tumor cells lose the metabolic advantage for fueling the proliferation through restoration of the pyruvate dehydrogenase (PDH) activity and subsequently promotion of pyruvic acid to enter the Krebs cycle in glioma. However, due to the lack of small molecule inhibitors of PGK1 kinase activity to treat glioma, whether PGK1 could be a therapeutic target of glioma has not been pharmacologically verified yet. In this study we developed a high-throughput screening and discovered that NG52, previously known as a yeast cell cycle-regulating kinase inhibitor, could inhibit the kinase activity of PGK1 (the IC = 2.5 ± 0.2 μM). We showed that NG52 dose-dependently inhibited the proliferation of glioma U87 and U251 cell lines with IC values of 7.8 ± 1.1 and 5.2 ± 0.2 μM, respectively, meanwhile it potently inhibited the proliferation of primary glioma cells. We further revealed that NG52 (12.5-50 μM) effectively inhibited the phosphorylation of PDHK1 at Thr338 site and the phosphorylation of PDH at Ser293 site in U87 and U251 cells, resulting in more pyruvic acid entering the Krebs cycle with increased production of ATP and ROS. Therefore, NG52 could reverse the Warburg effect by inhibiting PGK1 kinase activity, and switched cellular glucose metabolism from anaerobic mode to aerobic mode. In nude mice bearing patient-derived glioma xenograft, oral administration of NG52 (50, 100, 150 mg· kg·d, for 13 days) dose-dependently suppressed the growth of glioma xenograft. Together, our results demonstrate that targeting PGK1 kinase activity might be a potential strategy for glioma treatment.
抑制糖酵解过程一直是癌症治疗的一个有吸引力的方法，因为有证据表明肿瘤细胞更依赖糖酵解而不是氧化磷酸化途径。初步证据表明，抑制磷酸甘油酸激酶 1（PGK1）激酶活性可以逆转沃伯格效应，使肿瘤细胞失去通过恢复丙酮酸脱氢酶（PDH）活性和随后促进丙酮酸进入克雷布斯循环来为增殖提供燃料的代谢优势。然而，由于缺乏小分子抑制剂来治疗神经胶质瘤，PGK1 是否可以成为神经胶质瘤的治疗靶点尚未在药理学上得到验证。在这项研究中，我们开发了一种高通量筛选方法，并发现 NG52，以前被称为酵母细胞周期调节激酶抑制剂，能够抑制 PGK1 的激酶活性（IC50=2.5±0.2μM）。我们表明，NG52 剂量依赖性地抑制神经胶质瘤 U87 和 U251 细胞系的增殖，IC 值分别为 7.8±1.1 和 5.2±0.2μM，同时它也能有效地抑制原代神经胶质瘤细胞的增殖。我们进一步揭示，NG52（12.5-50μM）有效地抑制了 U87 和 U251 细胞中 PDHK1 在 Thr338 位点的磷酸化和 PDH 在 Ser293 位点的磷酸化，导致更多的丙酮酸进入克雷布斯循环，产生更多的 ATP 和 ROS。因此，NG52 通过抑制 PGK1 激酶活性可以逆转沃伯格效应，并将细胞葡萄糖代谢从无氧模式切换到有氧模式。在携带患者来源的神经胶质瘤异种移植的裸鼠中，NG52 的口服给药（50、100、150mg·kg·d，连续 13 天）剂量依赖性地抑制了神经胶质瘤异种移植的生长。总之，我们的研究结果表明，靶向 PGK1 激酶活性可能是治疗神经胶质瘤的一种潜在策略。
