中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
Pharmacologically inhibiting phosphoglycerate kinase 1 for glioma with NG52

文献类型:期刊论文

作者Wang, Wen-liang1,2; Jiang, Zong-ru1,2; Hu, Chen1; Chen, Cheng1,2; Hu, Zhen-quan1; Wang, Ao-li1; Wang, Li1,2; Liu, Jing1; Wang, Wen-chao1,3; Liu, Qing-song1,2,3,4
刊名ACTA PHARMACOLOGICA SINICA
出版日期2020-07-31
ISSN号1671-4083
关键词PGK1 NG52 kinase inhibitor Warburg effect glioma
DOI10.1038/s41401-020-0465-8
通讯作者Liu, Jing(jingliu@hmfl.ac.cn) ; Wang, Wen-chao(wwcbox@hmfl.ac.cn) ; Liu, Qing-song(qsliulab97@hmfl.ac.cn)
英文摘要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 mu M). We showed that NG52 dose-dependently inhibited the proliferation of glioma U87 and U251 cell lines with IC(50)values of 7.8 +/- 1.1 and 5.2 +/- 0.2 mu M, respectively, meanwhile it potently inhibited the proliferation of primary glioma cells. We further revealed that NG52 (12.5-50 mu M) 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 center dot kg(-1)center dot 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.
WOS关键词PROTEIN-KINASE ; UNITED-STATES ; PGK1 ; GLYCOLYSIS ; METABOLISM ; M2 ; DEHYDROGENASE ; PROGRESSION ; METASTASIS ; ADAPTATION
资助项目National Natural Science Foundation of China[81773777] ; National Natural Science Foundation of China[81673469] ; National Natural Science Foundation of China[81872748] ; National Natural Science Foundation of China[81803366] ; National Key Research and Development Program of China[2016YFA0400900] ; Natural Science Foundation of Anhui Province[1908085QH348] ; Science and Technology Major Projects of Anhui Province[17030801025] ; China Postdoctoral Science Foundation[2018T110634] ; China Postdoctoral Science Foundation[2018M630720] ; China Postdoctoral Science Foundation[2019M652057] ; Frontier Science Key Research Program of CAS[QYZDB-SSW-SLH037] ; CASHIPS Director's Fund[BJPY2019A03] ; Key Program of 13th FiveYear Plan of CASHIPS[KP-2017-26] ; National Program for Support of Top-Notch Young Professionals
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
出版者NATURE PUBLISHING GROUP
WOS记录号WOS:000554332300004
资助机构National Natural Science Foundation of China ; National Key Research and Development Program of China ; Natural Science Foundation of Anhui Province ; Science and Technology Major Projects of Anhui Province ; China Postdoctoral Science Foundation ; Frontier Science Key Research Program of CAS ; CASHIPS Director's Fund ; Key Program of 13th FiveYear Plan of CASHIPS ; National Program for Support of Top-Notch Young Professionals
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/102925]  
专题中国科学院合肥物质科学研究院
通讯作者Liu, Jing; Wang, Wen-chao; Liu, Qing-song
作者单位1.Chinese Acad Sci, Hefei Inst Phys Sci, High Magnet Field Lab, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei 230031, Peoples R China
2.Univ Sci & Technol China, Hefei 230036, Peoples R China
3.Precis Med Res Lab Anhui Prov, Hefei 230088, Peoples R China
4.Anhui Univ, Inst Phys Sci & Informat Technol, Key Lab Struct & Funct Regulat Hybrid Mat, Minist Educ, Hefei 230601, Peoples R China
推荐引用方式
GB/T 7714
Wang, Wen-liang,Jiang, Zong-ru,Hu, Chen,et al. Pharmacologically inhibiting phosphoglycerate kinase 1 for glioma with NG52[J]. ACTA PHARMACOLOGICA SINICA,2020.
APA Wang, Wen-liang.,Jiang, Zong-ru.,Hu, Chen.,Chen, Cheng.,Hu, Zhen-quan.,...&Liu, Qing-song.(2020).Pharmacologically inhibiting phosphoglycerate kinase 1 for glioma with NG52.ACTA PHARMACOLOGICA SINICA.
MLA Wang, Wen-liang,et al."Pharmacologically inhibiting phosphoglycerate kinase 1 for glioma with NG52".ACTA PHARMACOLOGICA SINICA (2020).

入库方式: OAI收割

来源:合肥物质科学研究院

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