Identification of the β-catenin/JNK/prothymosin-alpha axis as a novel target of sorafenib in hepatocellular carcinoma cells

被引:20
|
作者
Lin, Yi-Te [1 ]
Chao, Chuck C. -K. [1 ,2 ]
机构
[1] Chang Gung Univ, Grad Inst Biomed Sci, Coll Med, Taoyuan 33302, Taiwan
[2] Chang Gung Univ, Dept Biochem & Mol Biol, Coll Med, Taoyuan 33302, Taiwan
关键词
apoptosis; hepatocellular carcinoma; beta-catenin; prothymosin; sorafenib; PROTHYMOSIN-ALPHA; C-MYC; MESSENGER-RNA; CATENIN GENE; SOMATIC MUTATIONS; INDUCED APOPTOSIS; CROSS-RESISTANCE; CANCER-CELLS; COLON-CANCER; EXPRESSION;
D O I
10.18632/oncotarget.5738
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:38999 / 39017
页数:19
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