Abstract
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 IC50 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−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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Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grants 81773777, 81673469, 81872748, 81803366), the National Key Research and Development Program of China (Grant 2016YFA0400900), the Natural Science Foundation of Anhui Province (Grant 1908085QH348), the Science and Technology Major Projects of Anhui Province (Grant 17030801025), the China Postdoctoral Science Foundation (Grants 2018T110634, 2018M630720, 2019M652057), the Frontier Science Key Research Program of CAS (Grant QYZDB-SSW-SLH037), the CASHIPS Director’s Fund (Grant BJPY2019A03), and the Key Program of 13th Five-Year Plan of CASHIPS (Grant KP-2017-26). We are also grateful to the National Program for Support of Top-Notch Young Professionals for Jing Liu.
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QSL and JL designed the research. WLW, ZRJ, ALW, and CH developed the methodology. WLW, ZRJ, ZQH, and LW performed the experiments and collected the data. WLW, WCW, and QSL wrote the manuscript. LW, CC, and CH provided the experiment materials. QSL, WCW, and JL revised the manuscript.
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Wang, Wl., Jiang, Zr., Hu, C. et al. Pharmacologically inhibiting phosphoglycerate kinase 1 for glioma with NG52. Acta Pharmacol Sin 42, 633–640 (2021). https://doi.org/10.1038/s41401-020-0465-8
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DOI: https://doi.org/10.1038/s41401-020-0465-8
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