https://scholars.lib.ntu.edu.tw/handle/123456789/189804
Title: | Signal transducer and activator of transcription 3 is a major kinase- independent target of sorafenib in hepatocellular carcinoma=STAT3為 Sorafenib於肝癌的主要標的 | Authors: | TAI, WEI-TIEN CHENG, ANN-LII SHIAU, CHUNG-WAI HUANG, HSIANG-PO HUANG, JUI-WEN CHEN, PEI-JER CHEN, KUEN-FENG 鄭安理 陳培哲 |
Issue Date: | 2011 | Journal Volume: | v.55 | Start page/Pages: | 1041-1048 | Source: | Journal of Hepatology | Abstract: | Background& Aims: Recently, we reported that sorafenib sensitizes hepatocellular carcinoma (HCC) cells to TRAIL through the inhibition of signal transducer and activator of transcription 3 (STAT3). Here, we report that sorafenib inhibits HCC via a kinase-independent mechanism: SHP -1 dependent STAT3 inactivation. Methods: SC-1 is a sorafenib derivative that closely resembles sorafenib structurally but with no kinase inhibition activity. HCC cell lines (PLC5, Huh-7, Hep3B, and Sk-Hep1) were treated with sorafenib or SC-1 and apoptosis and signal transduction were analyzed. In vivo efficacy was determined in nude mice with Huh-7 xenografts. Results: SC-1 showed similar effects to sorafenib on growth inhibition and apoptosis in all tested HCC cell lines. SC-1 down-regulated phosphorylation of phospho-STAT3 (p-STAT3) at tyrosine 705 in all tested HCC cells. Expression of STAT3- driven genes, including Cyclin D1 and Survivin, was also repressed by SC-1. Luciferase reporter assay confirmed the inhibition of transcriptional activity of STAT3 in both sorafenib- treated and SC-1-treated cells. Ectopic expression of STAT3 in PLC5 cells abolished apoptosis in SC-1-treated cells. Sorafenib and SC-1 up-regulated SHP-1 activity. Knockdown of SHP-1, but not SHP-2 or PTP-1B, by small interference RNA reduced apoptosis induced by SC-1. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/240771 |
Appears in Collections: | 醫學系 |
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