|Title:||STAT3 mediates regorafenib-induced apoptosis in hepatocellular carcinoma||Authors:||Tai W.-T.
|Issue Date:||2014||Publisher:||American Association for Cancer Research Inc.||Journal Volume:||20||Journal Issue:||22||Start page/Pages:||5768-5776||Source:||Clinical Cancer Research||Abstract:||
Purpose: Here, we aim to investigate the molecular mechanism of regorafenib and verify the potential druggable target for the treatment of hepatocellular carcinoma (HCC). Experimental Design: HCC cell lines (PLC5, HepG2, Hep3B, SK-Hep1, and HA59T) were used to investigate the in vitro effect of regorafenib. Phosphatase activity was analyzed in HCC cells and purified SHP-1 proteins. PLC5-bearing mice were used to test the therapeutic efficiency of 20 and 40 mg/kg/d treatment with regorafenib (n ? 8 mice). The clinical relevance of STAT3 signaling was investigated with 142 tumor samples from different patients with HCC. Descriptive statistical analysis was used to compare the baseline characteristics of patients and the expression of p-STAT3. Results: Regorafenib inhibited STAT3-related signaling in a dose-dependent manner and was a more potent inhibitor of STAT3 than sorafenib. Regorafenib increased SHP-1 phosphatase activity in purified SHP-1 protein directly. N-SH2 domain deletion and D61A mutants mimicking open-form SHP-1 partially abolished regorafenib-induced STAT3 inhibition and apoptosis. Importantly, a higher level of expression of STAT3 was found in patients with advanced clinical stages (P = 0.009) and poorly differentiated tumors (P = 0.035). Conclusions: Regorafenib induced significant tumor inhibition by relieving the autoinhibited N-SH2 domain of SHP-1 directly and inhibiting p-STAT3 signals. STAT3 may be suitable as a prognostic marker of HCC development, and may be a druggable target for HCC-targeted therapy using regorafenib. ?2014 AACR.
|ISSN:||1078-0432||DOI:||10.1158/1078-0432.CCR-14-0725||SDG/Keyword:||phosphatase; protein SH2; protein tyrosine phosphatase SHP 1; regorafenib; STAT3 protein; antineoplastic agent; carbanilamide derivative; protein kinase inhibitor; protein tyrosine phosphatase SHP 1; pyridine derivative; regorafenib; STAT3 protein; adult; aged; animal experiment; animal model; antiangiogenic activity; apoptosis; Article; cancer staging; cell differentiation; concentration response; controlled study; drug mechanism; drug targeting; enzyme activity; enzyme inhibition; female; human; human cell; human tissue; in vitro study; in vivo study; liver cancer cell line; liver cell carcinoma; major clinical study; male; molecular mechanics; mouse; nonhuman; protein domain; protein expression; protein purification; signal transduction; tumor xenograft; animal; apoptosis; cancer grading; chemistry; comorbidity; disease course; disease model; drug effects; drug screening; liver cell carcinoma; liver tumor; metabolism; middle aged; pathology; Src homology domain; tumor cell line; Aged; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Comorbidity; Disease Models, Animal; Disease Progression; Female; Humans; Liver Neoplasms; Male; Mice; Middle Aged; Neoplasm Grading; Neoplasm Staging; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Pyridines; Signal Transduction; src Homology Domains; STAT3 Transcription Factor; Xenograft Model Antitumor Assays
|Appears in Collections:||基因體暨蛋白體醫學研究所|
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