Pharmacologically inhibiting phosphoglycerate kinase 1 for glioma with NG52
Pharmacologically inhibiting phosphoglycerate kinase 1 for glioma with NG52
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使用 NG52 对神经胶质瘤进行药理学抑制磷酸甘油酸激酶 1
DOI：
10.1038/s41401-020-0465-8
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发表时间：
2020-07
影响因子：
8.2
通讯作者：
Liu Qing-song
中科院分区：
文献类型：
--
作者：
Wang Wen-liang;Jiang Zong-ru;Hu Chen;Chen Cheng;Hu Zhen-quan;Wang Ao-li;Wang Li;Liu Jing;Wang Wen-chao;Liu Qing-song
由于肿瘤细胞更依赖于糖酵解而不是氧化磷酸化途径，因此抑制糖酵解过程已经成为癌症治疗的一种有吸引力的方法。初步证据显示，抑制磷酸甘油酸激酶1（PGK 1）激酶活性将逆转瓦尔堡效应，并使肿瘤细胞失去通过恢复丙酮酸脱氢酶（PDH）活性和随后促进葡糖酸进入胶质瘤中的克雷布斯循环而促进增殖的代谢优势。然而，由于目前尚缺乏针对PGK 1激酶活性的小分子抑制剂来治疗胶质瘤，PGK 1是否可以作为胶质瘤的治疗靶点尚未得到充分的证实。在本研究中，我们开发了一种高通量筛选，发现先前被称为酵母细胞周期调节激酶抑制剂的NG 52可以抑制PGK 1的激酶活性（IC 50 = 2.5 ± 0.2 μM）。NG 52对胶质瘤细胞系U87和U251的增殖具有剂量依赖性的抑制作用，其IC 50值分别为7.8 ± 1.1和5.2 ± 0.2 μM，同时对原代胶质瘤细胞的增殖具有明显的抑制作用。NG 52（12.5-50 μM）能有效抑制U87和U251细胞中PDHK 1在Thr 338位点的磷酸化和PDH在Ser 293位点的磷酸化，导致更多的磷酸进入Krebs循环，ATP和ROS的产生增加。因此，NG 52可通过抑制PGK 1激酶活性逆转瓦尔堡效应，使细胞葡萄糖代谢由无氧模式转变为有氧模式。在荷人源性胶质瘤裸鼠模型中，口服NG 52（50、100、150 mg· kg-1·d-1，连续13 d）呈剂量依赖性抑制胶质瘤移植瘤的生长。总之，我们的研究结果表明，靶向PGK 1激酶活性可能是胶质瘤治疗的潜在策略。
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 IC50= 2.5 ± 0.2 μM). We showed that NG52 dose-dependently inhibited the proliferation of glioma U87 and U251 cell lines with IC50values 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−1·d−1, 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.
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影响因子：
158.5
作者：
Stupp, R;Mason, WP;Ryan, G
通讯作者：
Ryan, G
PGK1乙酰化促进肝癌细胞增殖和肿瘤发生
影响因子：
13.5
作者：
Hu, Hongli;Zhu, Wenwei;Gao, Daming
通讯作者：
Gao, Daming
脓毒症中 PKM2 调节 Warburg 效应并促进 HMGB1 释放
影响因子：
16.6
作者：
Yang, Liangchun;Xie, Min;Yang, Minghua;Yu, Yan;Zhu, Shan;Hou, Wen;Kang, Rui;Lotze, Michael T.;Billiar, Timothy R.;Wang, Haichao;Cao, Lizhi;Tang, Daolin
通讯作者：
Tang, Daolin
DOI：
10.1038/nrc.2016.84
发表时间：
2016-09-23
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Nakazawa MS;Keith B;Simon MC
通讯作者：
Simon MC
影响因子：
15.9
作者：
Dolecek, Therese A.;Propp, Jennifer M.;Kruchko, Carol
通讯作者：
Kruchko, Carol