HSP90抑制剂抑制糖酵解并促进小鼠肝癌细胞系H22凋亡

基础医学与临床 ›› 2020, Vol. 40 ›› Issue (7): 912-916.

HSP90抑制剂抑制糖酵解并促进小鼠肝癌细胞系H22凋亡

刘娜斯, 曹明月, 吴友明, 黄薇, 杨楠, 刘雁勇^*

中国医学科学院基础医学研究所北京协和医学院基础学院药理学系,北京 100005

收稿日期:2020-04-25 修回日期:2020-05-17 出版日期:2020-07-05 发布日期:2020-06-29
通讯作者: ^*yanyongliu@ ibms.pumc.edu.cn
基金资助:
国家科技重大专项(2019ZX09301170);国家自然科学基金(81972688);北京市自然科学基金(7172134,7192128);中国医学科学院医学与健康科技创新工程(2016-I2M-3-004);协和青年科研基金与中央高校基本科研业务费专项基金(3332015113,2017350002)

HSP90 inhibitor inhibits glycolysis and promotes apoptosis of mouse hepatocarcinoma cell line H22

LIU Na-si, CAO Ming-yue, WU You-ming, HUANG Wei, YANG Nan, LIU Yan-yong^*

Department of Pharmacology, Institute of Basic Medical Sciences CAMS, School of Basic Medicine PUMC, Beijing 100005, China

Received:2020-04-25 Revised:2020-05-17 Online:2020-07-05 Published:2020-06-29
Contact: ^*yanyongliu@ ibms.pumc.edu.cn

摘要/Abstract

摘要： 目的探讨热休克蛋白HSP90抑制剂对小鼠肝癌细胞糖酵解和细胞凋亡的影响及其潜在的作用机制。方法皮质酮(CORT)、糖皮质激素受体(GR)拮抗剂RU486和HSP90抑制剂17-AAG处理小鼠肝癌细胞系H22后检测乳酸和ATP水平;流式细胞仪检测H22细胞凋亡;CORT、RU486和17-AAG分别处理H22细胞,利用Western blot检测GR及PI3K/Akt通路相关蛋白表达。结果与对照组相比,CORT促进GR核转位,RU486使其水平降低,与CORT单独处理相比,CORT与17-AAG共处理可抑制CORT对GR核转位的促进作用(P＜0.05);CORT处理后乳酸和ATP水平显著升高(P＜0.05),与17-AAG共处理后此作用被显著抑制(P＜0.05),乳酸和ATP水平分别下降了24%和17%;17-AAG可显著升高H22细胞总凋亡率,呈现剂量依赖性(P＜0.05);与对照组相比,CORT显著上调pAkt表达水平,与17-AAG共处理后表达水平显著下降(P＜0.05)。结论 HSP90抑制剂17-AAG通过抑制GR核转位从而抑制糖酵解并促进肝癌细胞系凋亡,其机制可能与对PI3K / Akt通路的调控有关。

关键词: 肝细胞癌, HSP90抑制剂, 糖酵解

Abstract: Objective To investigate the effect of HSP90 inhibitor on glycolysis and apoptosis in mouse hepatocarcinoma cells, and to explore its underlying mechanism. Methods Examine the level of lactate and ATP in mouse hepatoma cell line H22 treated with CORT, GR antagonist RU486 and HSP90 inhibitor 17-AAG; Evaluate the apoptosis level of H22 cells after CORT or various concentrations of 17-AAG treatment; H22 cells were treated with CORT, RU486 and 17-AAG respectively, and then the expression of GR and PI3K/Akt-related proteins was determined by Western blot. Results Compared with the control group, CORT promoted GR nuclear translocation, while inhibited after RU486 treatment. Compared with CORT treatment alone, CORT and 17-AAG co-treatment could weaken the promotion of GR nuclear translocation by CORT(P＜0.05); The level of lactate and ATP was increased significantly after CORT treatment (P＜0.05). After co-treatment with 17-AAG, this effect was inhibited (P＜0.05).And the level of lactate and ATP was decreased by 24% and 17% respectively; Compared with the control group, 17-AAG could significantly increase the total apoptosis rate of H22 cells in a dose-dependent manner(P＜0.05); Compared with the control group, the protein expression of pAkt increased after CORT treatment, while decreased significantly after co-treatment with 17-AAG (P＜0.05). Conclusions HSP90 inhibitor 17-AAG can inhibit GR nuclear translocation, thereby inhibit glycolysis and promote apoptosis of hepatocarcinoma cells, which is potentially regulated by PI3K/Akt pathway.

Key words: hepatocellular carcinoma, HSP90 inhibitor, glycolysis

中图分类号:

R735.7

刘娜斯, 曹明月, 吴友明, 黄薇, 杨楠, 刘雁勇. HSP90抑制剂抑制糖酵解并促进小鼠肝癌细胞系H22凋亡[J]. 基础医学与临床, 2020, 40(7): 912-916.

LIU Na-si, CAO Ming-yue, WU You-ming, HUANG Wei, YANG Nan, LIU Yan-yong. HSP90 inhibitor inhibits glycolysis and promotes apoptosis of mouse hepatocarcinoma cell line H22[J]. Basic & Clinical Medicine, 2020, 40(7): 912-916.

参考文献

[1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020[J]. CA Cancer J Clin, 2020,70:7-30.
[2] Nishikawa T, Bellance N, Damm A, et al. A switch in the source of ATP production and a loss in capacity to perform glycolysis are hallmarks of hepatocyte failure in advance liver disease[J]. J Hepatol, 2014,60:1203-1211.
[3] Maximchik P, Abdrakhmanov A, Inozemtseva E, et al. 2-Deoxy-D-glucose has distinct and cell line-specific effects on the survival of different cancer cells upon antitumor drug treatment[J]. FEBS J, 2018,285:4590-4601.
[4] Kirschke E, Goswami D, Southworth D, et al. Glucocorticoid receptor function regulated by coordinated action of the Hsp90 and Hsp70 chaperone cycles [J]. Cell, 2014, 157:1685-1697.
[5] Hendrick JP, Hartl FU. Molecular chaperone functions of heat-shock proteins[J]. Annu Rev Biochem, 1993,62:349-384.
[6] Huang W, Dong Z, Wang F, et al. A small molecule compound targeting STAT3 DNA-binding domain inhibits cancer cell proliferation, migration, and invasion[J]. ACS Chem Biol, 2014,9:1188-1196.
[7] Riebold M, Kozany C, Freiburger L, et al. A C-terminal HSP90 inhibitor restores glucocorticoid sensitivity and relieves a mouse allograft model of Cushing disease[J]. Nat Med, 2015,21:276-280.
[8] Whitesell L, Cook P. Stable and specific binding of heat shock protein 90 by geldanamycin disrupts glucocorticoid receptor function in intact cells[J]. Mol Endocrinol, 1996,10:705-712.
[9] Jiang T, Zhou ML, Fan J. Inhibition of GLUT-1 expression and the PI3K/Akt pathway to enhance the chemosensitivity of laryngeal carcinoma cells in vitro[J]. Onco Targets Ther, 2018,11:7865-7872.
[10] Zhao Y, Yang L, He J, et al. STYK1 promotes Warburg effect through PI3K/AKT signaling and predicts a poor prognosis in nasopharyngeal carcinoma[J]. Tumor Biol, 2017,39:1-8.
[11] Giulino-Roth L, van Besien HJ, Dalton T, et al. Inhibit-ion of Hsp90 suppresses PI3K/AKT/mTOR signaling and Has antitumor activity in Burkitt lymphoma[J]. Mol Cancer Ther, 2017,16:1779-1790.

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