(20S) Ginsenoside Rh2 Exerts Its Anti-Tumor Effect by Disrupting the HSP90A-Cdc37 System in Human Liver Cancer Cells.
(20S) Ginsenoside Rh2 Exerts Its Anti-Tumor Effect by Disrupting the HSP90A-Cdc37 System in Human Liver Cancer Cells.
复制标题
DOI：
10.3390/ijms222313170
复制
发表时间：
2021-12-06
影响因子：
5.6
通讯作者：
Jin YH
中科院分区：
文献类型：
--
作者：
Chen C;Wang YS;Zhang ET;Li GA;Liu WY;Li Y;Jin YH
(20S)人参皂苷Rh2 (G-Rh2)是人参的主要生物活性代谢物，有效抑制人肝癌细胞的存活和增殖。然而，其分子靶点和作用机制仍然很大程度上未知。令人兴奋的是，我们通过噬菌体展示分析和质谱筛选出与肝癌相关的关键调节蛋白热休克蛋白90α（HSP90A）作为（20S）G-Rh2的潜在靶标。分子对接和热位移分析表明(20S)G-Rh2直接与HSP90A结合，并且这种结合被证实抑制HSP90A与其共伴侣细胞分裂周期控制蛋白37(Cdc37)之间的相互作用。众所周知，HSP90A-Cdc37 系统有助于细胞周期蛋白依赖性激酶 (CDK) 的折叠和成熟。正如预期的那样，CDK4 和 CDK6（两种 G0-G1 相促进激酶）以及 CDK2（一种关键的 G1-S 相变促进激酶）在 (20S) G-Rh2 处理后显着下调，并且这些下调是由蛋白酶体途径介导的。在相同条件下，细胞周期停滞在G0-G1期，并且(20S)G-Rh2处理显着抑制细胞生长。综上所述，这项研究首次揭示了(20S) G-Rh2通过靶向HSP90A从而扰乱HSP90A-Cdc37伴侣系统来发挥抗肿瘤作用。 HSP90A在人肝癌细胞中频繁过度表达，其高表达与肝癌患者的不良预后密切相关。因此，(20S)G-Rh2可能成为肝癌治疗的有前途的替代药物。
(20S) ginsenoside Rh2 (G-Rh2), a major bioactive metabolite of ginseng, effectively inhibits the survival and proliferation of human liver cancer cells. However, its molecular targets and working mechanism remain largely unknown. Excitingly, we screened out heat shock protein 90 alpha (HSP90A), a key regulatory protein associated with liver cancer, as a potential target of (20S) G-Rh2 by phage display analysis and mass spectrometry. The molecular docking and thermal shift analyses demonstrated that (20S) G-Rh2 directly bound to HSP90A, and this binding was confirmed to inhibit the interaction between HSP90A and its co-chaperone, cell division cycle control protein 37 (Cdc37). It is well-known that the HSP90A-Cdc37 system aids in the folding and maturation of cyclin-dependent kinases (CDKs). As expected, CDK4 and CDK6, the two G0-G1 phase promoting kinases as well as CDK2, a key G1-S phase transition promoting kinase, were significantly downregulated with (20S) G-Rh2 treatment, and these downregulations were mediated by the proteasome pathway. In the same condition, the cell cycle was arrested at the G0-G1 phase and cell growth was inhibited significantly by (20S) G-Rh2 treatment. Taken together, this study for the first time reveals that (20S) G-Rh2 exerts its anti-tumor effect by targeting HSP90A and consequently disturbing the HSP90A-Cdc37 chaperone system. HSP90A is frequently overexpressed in human hepatoma cells and the higher expression is closely correlated to the poor prognosis of liver cancer patients. Thus, (20S) G-Rh2 might become a promising alternative drug for liver cancer therapy.
登录
查看更多内容
影响因子：
3.8
作者：
Ji CH;Kwon YT
通讯作者：
Kwon YT
影响因子：
7.3
作者：
Bhat, Rohit;Tummalapalli, Sreedhar R.;Rotella, David P.
通讯作者：
Rotella, David P.
影响因子：
14.9
作者：
Edgar, R;Domrachev, M;Lash, AE
通讯作者：
Lash, AE
影响因子：
9.7
作者：
Li, Binghui;Zhao, Jiong;Wang, Chong-Zhi;Searle, Jennifer;He, Tong-Chuan;Yuan, Chun-Su;Du, Wei
通讯作者：
Du, Wei
影响因子：
9.7
作者：
Lee, KY;Park, JA;Lee, SK
通讯作者：
Lee, SK