https://scholars.lib.ntu.edu.tw/handle/123456789/502698
標題: | Induction of DNA damage-inducible gene GADD45β contributes to sorafenib-induced apoptosis in hepatocellular carcinoma cells | 作者: | DA-LIANG OU Ying-Chun Shen SUNG-LIANG YU Chen K.-F. Yeh P.-Y. Fan H.-H. Feng W.-C. Wang C.-T. LIANG-IN LIN CHIUN HSU ANN-LII CHENG |
公開日期: | 2010 | 卷: | 70 | 期: | 22 | 起(迄)頁: | 9309-9318 | 來源出版物: | Cancer Research | 摘要: | Markers that could accurately predict responses to the general kinase inhibitor sorafenib are needed to better leverage its clinical applications. In this study, we examined a hypothesized role in the drug response for the growth arrest DNA damage-inducible gene 45β (GADD45β), which is commonly underexpressed in hepatocellular carcinoma (HCC) where sorafenib may offer an important new therapeutic option. The anticancer activity of sorafenib-induced GADD45β expression was tested in a panel of HCC cell lines and xenograft models. We found that GADD45β mRNA and protein expression were induced relatively more prominently in HCC cells that were biologically sensitive to sorafenib treatment. GADD45β induction was not found after treatment with either the mitogen-activated protein kinase-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126 or the Raf inhibitor ZM336372, suggesting that GADD45β induction by sorafenib was independent of Raf/MEK/ERK signaling activity. However, c-Jun NH2-terminal kinase (JNK) kinase activation occurred preferentially in sorafenib-sensitive cells. Small interfering RNA-mediated knockdown of GADD45β or JNK kinase limited the proapoptotic effects of sorafenib in sorafenib-sensitive cells. We defined the -339/-267 region in the GADD45β promoter containing activator protein-1 and SP1-binding sites as a crucial region for GADD45β induction by sorafenib. Together, our findings suggest that GADD45β induction contributes to sorafenib-induced apoptosis in HCC cells, prompting further studies to validate its potential value in predicting sorafenib efficacy. ?2010 AACR. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/502698 | ISSN: | 0008-5472 | DOI: | 10.1158/0008-5472.CAN-10-1033 | SDG/關鍵字: | 1,4 diamino 1,4 bis(2 aminophenylthio) 2,3 dicyanobutadiene; GADD45 beta; messenger RNA; mitogen activated protein kinase; n [5 (3 dimethylaminobenzamido) 2 methylphenyl] 4 hydroxybenzamide; Raf protein; small interfering RNA; sorafenib; stress activated protein kinase; transcription factor; transcription factor AP 1; transcription factor Sp1; unclassified drug; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; article; binding site; cancer cell; controlled study; drug efficacy; drug response; drug sensitivity; gene expression; gene induction; human; human cell; hypothesis; liver cell carcinoma; male; mouse; nonhuman; priority journal; promoter region; signal transduction; tumor xenograft; validation process; Animals; Anthracenes; Antigens, Differentiation; Antineoplastic Agents; Apoptosis; Benzenesulfonates; Binding Sites; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; JNK Mitogen-Activated Protein Kinases; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Promoter Regions, Genetic; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Sp1 Transcription Factor; Transcription Factor AP-1; Transplantation, Heterologous |
顯示於: | 醫學檢驗暨生物技術學系 |
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