Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3
Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3作者机构:Liver Cancer Institute Zhongshan Hospital and Shanghai Medical School Fudan University Shanghai 200032 China.
出 版 物:《World Journal of Gastroenterology》 (世界胃肠病学杂志(英文版))
年 卷 期:2011年第17卷第34期
页 面:3922-3932页
核心收录:
学科分类:1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金:Supported by Grants from the China 863 Project, No. 2007A-A02Z479 the National Natural Science Foundation of China, No. 30972949 and 30901432 Shanghai Rising-Star Program, No. 10QA1401300 Research Fund for the Doctoral Program of Higher Education of China, No. 20090071120026
主 题:STAT3 细胞生长 肝癌 Janus激酶 细胞外信号调节激酶 去磷酸化 磷脂酰肌醇-3 信号转导
摘 要:AIM: To investigate the inhibitory role and the underlying mechanisms of sorafenib on signal transducer and activator of transcription 3 (STAT3) activity in hepatocellular carcinoma (HCC).METHODS: Human and rat HCC cell lines were treated with sorafenib. Proliferation and STAT3 dephosphorylation were assessed. Potential molecular mechanisms of STAT3 pathway inhibition by sorafenib were evaluated. In vivo antitumor action and STAT3 inhibition were investigated in an immunocompetent orthotopic rat HCC ***: Sorafenib decreased STAT3 phosphorylationat the tyrosine and serine residues (Y705 and S727), but did not affect Janus kinase 2 (JAK2) and phosphatase shatterproof 2 (SHP2), which is associated with growth inhibition in HCC cells. Dephosphorylation of S727 was associated with attenuated extracellular signal-regulated kinase (ERK) phosphorylation, similar to the effects of a mitogen-activated protein kinase (MEK) inhibitor U0126, suggesting that sorafenib induced S727 dephosphorylation by inhibiting MEK/ERK signaling. Meanwhile, sorafenib could also inhibit Akt phosphorylation, and both the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and Akt knockdown resulted in Y705 dephosphorylation, indicating that Y705 dephosphorylation by sorafenib was mediated by inhibiting the PI3K/Akt pathway. Finally, in the rat HCC model, sorafenib signifi cantly inhibited STAT3 activity, reducing tumor growth and ***: Sorafenib inhibits growth and metastasis of HCC in part by blocking the MEK/ERK/STAT3 and PI3K/Akt/STAT3 signaling pathways, but independent of JAK2 and SHP2 activation.