EH-42：一种新型小分子通过抑制 STAT3 信号通路诱导肝癌细胞凋亡并抑制其迁移和侵袭。

EH-42: A Novel Small Molecule Induces Apoptosis and Inhibits Migration and Invasion of Human Hepatoma Cells through Suppressing STAT3 Signaling Pathway.

机构信息

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.

Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.

出版信息

Curr Cancer Drug Targets. 2019;19(7):583-593. doi: 10.2174/1568009619666181226094814.

DOI:10.2174/1568009619666181226094814

PMID:30585547

Abstract

BACKGROUND

Since signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in hepatocellular carcinoma (HCC) and plays a key role in this tumor progression. Inhibition of the STAT3 signaling pathway has been considered as an effective therapeutic strategy for suppressing HCC development.

OBJECTIVE

In this study, we investigated the anti-cancer effects of EH-42 on HCC cells and tried to explain the underlying mechanism.

METHODS

MTT assay, colon formation assay and AnnexinV-FITC/PI double-staining assay were performed to assess the effects of EH-42 on cell growth and survival. Wound healing assay and transwell invasion assay were performed to assess the effects of EH-42 on cell migration and invasion. Western blotting assay was performed to analyze the effects of EH-42 on relative proteins.

RESULTS

According to the MTT assay, colon formation assay and AnnexinV-FITC/PI doublestaining assay, EH-42 could suppress the growth and induce apoptosis of HCC cells in a dosedependent manner. Further western blotting assay showed that the inhibitory effects of EH-42 on cell growth and survival were caused by activating caspase 3/9, suppressing the phospho-STAT3 (Tyr 705) and downregulating anti-apoptotic proteins like Bcl-2/Bcl-xL. Moreover, migration and invasion abilities of HCC cells were also inhibited by EH-42 in the wound healing assay and transwell invasion assay. The potential mechanism was that EH-42 could inhibit HCC metastasis via reversing epithelial-mesenchymal transition and downregulating the secretion of MMPs.

CONCLUSION

Taken together, these findings suggested that EH-42 could be a potential therapeutic agent for HCC treatment.

摘要

背景

信号转导子和转录激活子 3（STAT3）在肝细胞癌（HCC）中异常激活，并且在肿瘤进展中发挥关键作用。抑制 STAT3 信号通路已被认为是抑制 HCC 发展的有效治疗策略。

目的

本研究旨在探讨 EH-42 对 HCC 细胞的抗癌作用，并试图解释其潜在机制。

方法

采用 MTT 法、集落形成实验和 AnnexinV-FITC/PI 双染实验评估 EH-42 对细胞生长和存活的影响。采用划痕愈合实验和 Transwell 侵袭实验评估 EH-42 对细胞迁移和侵袭的影响。采用 Western blot 实验分析 EH-42 对相关蛋白的影响。

结果

根据 MTT 法、集落形成实验和 AnnexinV-FITC/PI 双染实验，EH-42 能够以剂量依赖的方式抑制 HCC 细胞的生长并诱导其凋亡。进一步的 Western blot 实验表明，EH-42 对细胞生长和存活的抑制作用是通过激活 caspase 3/9、抑制磷酸化 STAT3（Tyr 705）和下调抗凋亡蛋白如 Bcl-2/Bcl-xL 引起的。此外，EH-42 还可以通过逆转上皮间质转化和下调 MMPs 的分泌来抑制 HCC 细胞的迁移和侵袭能力。