Protopanaxadiol inhibits epithelial-mesenchymal transition of hepatocellular carcinoma by targeting STAT3 pathway
Protopanaxadiol inhibits epithelial-mesenchymal transition of hepatocellular carcinoma by targeting STAT3 pathway
复制标题
原人参二醇通过靶向STAT3通路抑制肝细胞癌上皮间质转化
DOI：
10.1038/s41419-019-1733-8
复制
发表时间：
2019
影响因子：
9
通讯作者：
Yang Cheng
中科院分区：
文献类型：
--
作者：
Yang Lan;Zhang Xue ying;Li Kun;Li An ping;Yang Wen dong;Yang Ru;Wang Peng;Zhao Zi han;Cui Fang;Qin Yuan;Yang Jia huan;Tao Hong lian;Sun Tao;Chen Shuang;Yu Pei hua;Liu Hui juan;Yang Cheng
二醇型人参皂苷，如原人参二醇（PPD），表现出抗氧化、抗炎和抗肿瘤作用。然而，这些皂甙的抗肿瘤作用和PPD的机制尚不清楚。在这项工作中，几种衍生物，包括PPD，Rg 5，Rg 3，Rh 2和Rh 3，在五种不同的癌细胞系中的抗肿瘤作用进行了评估。PPD对5种肿瘤细胞增殖和迁移的抑制作用最强，尤其是对肝细胞癌（HCC）细胞的抑制作用最强。因此，PPD在HCC细胞中的作用机制被阐明。PPD对HepG 2和PLC/PRF/5细胞的增殖、迁移和侵袭能力有明显的抑制作用，且呈剂量依赖性。Western blot和免疫荧光检测显示PPD可改变上皮-间质转化标志物的表达，增加E-cadherin的表达，降低vimentin的表达。对接和biacore实验表明STAT 3是PPD的靶蛋白，其与STAT 3的SH 2结构域的Gly 583/Leu 608/Tyr 674形成氢键。PPD抑制STAT 3的磷酸化及其从胞质到细胞核的易位，从而抑制Twist 1的表达。PPD还抑制PLC/PRF/5异种移植瘤的肿瘤体积和肿瘤肺转移。结论PPD可通过STAT 3/Twist 1通路抑制肝癌细胞的增殖和转移。
Diol-type ginsenosides, such as protopanaxadiol (PPD), exhibit antioxidation, anti-inflammation, and antitumor effects. However, the antitumor effect of these ginsenosides and the mechanism of PPD remain unclear. In this work, the antitumor effects of several derivatives, including PPD, Rg5, Rg3, Rh2, and Rh3, were evaluated in five different cancer cell lines. PPD demonstrated the best inhibitory effects on the proliferation and migration of the five cancer cell lines, especially the hepatocellular carcinoma (HCC) cell lines. Therefore, the mechanism of action of PPD in HCC cells was elucidated. PPD inhibited the proliferation, migration, and invasion ability of HepG2 and PLC/PRF/5 cells in a dose-dependent manner. Western blot and immunofluorescence assay showed that PPD can alter the expression of epithelial–mesenchymal transition markers, increase E-cadherin expression, and decrease vimentin expression. Docking and biacore experiments revealed that STAT3 is the target protein of PPD, which formed hydrogen bonds with Gly583/Leu608/Tyr674 at the SH2 domain of STAT3. PPD inhibited the phosphorylation of STAT3 and its translocation from the cytosol to the nucleus, thereby inhibiting the expression of Twist1. PPD also inhibited tumor volume and tumor lung metastasis in PLC/PRF/5 xenograft model. In conclusion, PPD can inhibit the proliferation and metastasis of HCC cells through the STAT3/Twist1 pathway.