Identification of the β-catenin/JNK/prothymosin-alpha axis as a novel target of sorafenib in hepatocellular carcinoma cells.
Sorafenib is a kinase inhibitor used as anticancer drug against various human tumors, including advanced hepatocellular carcinoma (HCC). β-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 β-catenin and PTMA in a dose-dependent manner. Silencing β-catenin reduces PTMA level and sensitizes HCC cells to sorafenib. In contrast, ectopic expression of β-catenin induces PTMA expression and cell resistance to the drug. Sorafenib inhibits PTMA expression at the transcriptional level by inhibiting the β-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 β-catenin modulation of gene transcription in response to sorafenib. In addition, chemical inhibitors that target JNK abrogate β-catenin/AP-1 binding to the endogenous PTMA gene and reduces PTMA transcription and protein expression. Silencing of β-catenin or c-Fos induces similar effects on gene regulation and these are reversed by ectopic expression of β-catenin. Mutations in the PTMA promoter at the predicted β-catenin/AP-1 binding site partly abrogate sorafenib's effects on PTMA transcription. These results indicate that PTMA is induced by the oncoprotein β-catenin and protects HCC cells against sorafenib-induced cell death. The β-catenin/JNK/PTMA axis may thus represent a novel target for chemotherapy against HCC.
['Lin|Yi-Te|YT|', 'Chao|Chuck C-K|CC|']
D000970:Antineoplastic Agents D017209:Apoptosis D006528:Carcinoma, Hepatocellular D045744:Cell Line, Tumor D049109:Cell Proliferation D006801:Humans D008113:Liver Neoplasms D020935:MAP Kinase Signaling System D009536:Niacinamide D010671:Phenylurea Compounds D011498:Protein Precursors D000077157:Sorafenib D013947:Thymosin D014162:Transfection D051176:beta Catenin
β-catenin sorafenib hepatocellular carcinoma prothymosin apoptosis