Sorafenib is a kinase inhibitor used as anticancer drug against various human tumors, including advanced hepatocellular carcinoma (HCC). beta-Catenin and prothymosin alpha (PTMA) are overexpressed in HCC and other tumors. Previous studies have shown that PTMA expression modulates the response of HCC cells to sorafenib. However, the underlying mechanism of PTMA activity in this context remains unclear. We show here that sorafenib inhibits both beta-Catenin and PTMA in a dose-dependent manner. Silencing beta-Catenin reduces PTMA level and sensitizes HCC cells to sorafenib. In contrast, ectopic expression of beta-Catenin induces PTMA expression and cell resistance to the drug. Sorafenib inhibits PTMA expression at the transcriptional level by inhibiting the beta-Catenin pathway. Nucleotide deletion analysis of the PTMA gene promoter reveals that a DNA segment lying 1,500-1,600 bp upstream of the PTMA transcription start site represents an AP-1-binding site that is critical for beta-Catenin modulation of gene transcription in response to sorafenib. In addition, chemical inhibitors that target JNK abrogate beta-Catenin/AP-1 binding to the endogenous PTMA gene and reduces PTMA transcription and protein expression. Silencing of beta-Catenin or c-Fos induces similar effects on gene regulation and these are reversed by ectopic expression of beta-Catenin. Mutations in the PTMA promoter at the predicted beta-Catenin/AP-1 binding site partly abrogate sorafenib's effects on PTMA transcription. These results indicate that PTMA is induced by the oncoprotein beta-Catenin and protects HCC cells against sorafenib-induced cell death. The beta-Catenin/JNK/PTMA axis may thus represent a novel target for chemotherapy against HCC.
机构:
Guangxi Med Univ Canc Hosp, Res Dept, Nanning, Peoples R China
Guangxi Med Univ, Nanning, Peoples R ChinaGuangxi Med Univ Canc Hosp, Res Dept, Nanning, Peoples R China
Wu, Manya
Shen, Xiaoyun
论文数: 0引用数: 0
h-index: 0
机构:
Zhejiang Univ, Sir Run Run Shaw Hosp, Sch Med, Dept Expt Res, Hangzhou, Peoples R ChinaGuangxi Med Univ Canc Hosp, Res Dept, Nanning, Peoples R China
Shen, Xiaoyun
Tang, Yanping
论文数: 0引用数: 0
h-index: 0
机构:
Guangxi Med Univ Canc Hosp, Res Dept, Nanning, Peoples R ChinaGuangxi Med Univ Canc Hosp, Res Dept, Nanning, Peoples R China
Tang, Yanping
Zhou, Caifu
论文数: 0引用数: 0
h-index: 0
机构:
Guangxi Med Univ Canc Hosp, Res Dept, Nanning, Peoples R ChinaGuangxi Med Univ Canc Hosp, Res Dept, Nanning, Peoples R China
Zhou, Caifu
Li, Haixia
论文数: 0引用数: 0
h-index: 0
机构:
Guangxi Med Univ, Nanning, Peoples R ChinaGuangxi Med Univ Canc Hosp, Res Dept, Nanning, Peoples R China
Li, Haixia
Luo, Xiaoling
论文数: 0引用数: 0
h-index: 0
机构:
Guangxi Med Univ Canc Hosp, Res Dept, Nanning, Peoples R ChinaGuangxi Med Univ Canc Hosp, Res Dept, Nanning, Peoples R China
机构:
Sichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R ChinaSichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
Ren, Fenglian
Wu, Hong
论文数: 0引用数: 0
h-index: 0
机构:
Sichuan Univ, W China Hosp, Dept Hepatobiliary Pancreat Surg, Chengdu 610041, Peoples R ChinaSichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
Wu, Hong
Lei, Yunlong
论文数: 0引用数: 0
h-index: 0
机构:
Sichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R ChinaSichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
Lei, Yunlong
Zhang, Haiyuan
论文数: 0引用数: 0
h-index: 0
机构:
Yangtze Univ, Sch Med, Shashi 434000, Hubei, Peoples R ChinaSichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
Zhang, Haiyuan
Liu, Rui
论文数: 0引用数: 0
h-index: 0
机构:
Sichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R ChinaSichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
Liu, Rui
Zhao, Yong
论文数: 0引用数: 0
h-index: 0
机构:
Sichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R ChinaSichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
Zhao, Yong
Chen, Xiancheng
论文数: 0引用数: 0
h-index: 0
机构:
Sichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R ChinaSichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
Chen, Xiancheng
Zeng, Dequan
论文数: 0引用数: 0
h-index: 0
机构:
Sichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R ChinaSichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
Zeng, Dequan
Tong, Aiping
论文数: 0引用数: 0
h-index: 0
机构:
Sichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R ChinaSichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
Tong, Aiping
Chen, Lijuan
论文数: 0引用数: 0
h-index: 0
机构:
Sichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R ChinaSichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
Chen, Lijuan
Wei, Yuquan
论文数: 0引用数: 0
h-index: 0
机构:
Sichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R ChinaSichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
Wei, Yuquan
Huang, Canhua
论文数: 0引用数: 0
h-index: 0
机构:
Sichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R ChinaSichuan Univ, W China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China