https://scholars.lib.ntu.edu.tw/handle/123456789/484022
標題: | Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression | 作者: | CHIUN HSU LIANG-IN LIN Cheng, Yu-Che Feng, Zi-Rui YU-YUN SHAO ANN-LII CHENG DA-LIANG OU |
公開日期: | 2016 | 卷: | 22 | 期: | 10 | 來源出版物: | Clinical Cancer Research | 摘要: | © 2016 American Association for Cancer Research. Purpose: To clarify the effects of cyclin E1 suppression on antitumor efficacy of sorafenib in hepatocellular carcinoma cells and to explore the potential of combining sorafenib with cyclindependent kinase (CDK) inhibition in therapy. Experimental Design: The effects of cyclin E1 suppression on sorafenib-induced apoptosis were tested in both sorafenibsensitive (Huh-7 and HepG2, IC50 5-6 mmol/L) and sorafenib-resistant (Huh-7R and HepG2R, IC50 14-15 mmol/L) hepatocellular carcinoma cells. The activity of pertinent signaling pathways and the expression of cell cycle and apoptosisrelated proteins were measured using Western blotting. Efficacy of sorafenib combined with the pan-CDK inhibitor flavopiridol was tested both in vitro and in xenograft experiments. The pertinent downstream mediators of antitumor efficacy were tested in transient transfection and RNA interference experiments. Results: Cyclin E1 mRNA and protein expressions were suppressed after sorafenib treatment in sorafenib-sensitive but not in sorafenib-resistant hepatocellular carcinoma cells. Changes in cyclin E2 or D1 were not correlated with sorafenib sensitivity. The knockdown of cyclin E1 expression reversed the resistance of hepatocellular carcinoma cells to sorafenib in terms of cell growth and apoptosis induction, whereas the overexpression of cyclin E1 increased the resistance to sorafenib. The growth-inhibitory and apoptosis-inducing effects of sorafenib were enhanced by flavopiridol, and Mcl-1 suppression was determined to play a critical role in mediating this enhancing effect. Conclusions: The cyclin E1 suppression in hepatocellular carcinoma cells may serve as a pharmacodynamic biomarker for predicting sorafenib efficacy. The combination of sorafenib and CDK inhibitors may improve the efficacy of sorafenib in hepatocellular carcinoma. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/484022 | ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-15-0499 35859493 |
SDG/關鍵字: | cyclin D1; cyclin dependent kinase; cyclin E; flavopiridol; protein mcl 1; RNA; sorafenib; carbanilamide derivative; CCNE1 protein, human; cyclin E; MCL1 protein, human; messenger RNA; nicotinamide; oncoprotein; protein kinase inhibitor; protein mcl 1; sorafenib; animal cell; animal experiment; antineoplastic activity; apoptosis; Article; cancer cell; cell cycle; cell growth; controlled study; down regulation; drug efficacy; enzyme inhibition; HepG2 cell line; human; human cell; IC50; in vitro study; in vivo study; liver cell carcinoma; male; mouse; nonhuman; priority journal; protein expression; RNA interference; sensitivity analysis; tumor xenograft; Western blotting; analogs and derivatives; animal; antagonists and inhibitors; Bagg albino mouse; cell proliferation; drug effects; drug resistance; drug screening; Hep-G2 cell line; liver cell carcinoma; liver tumor; metabolism; nude mouse; procedures; signal transduction; tumor cell line; Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclin E; Drug Resistance, Neoplasm; Hep G2 Cells; Humans; Liver Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein; Niacinamide; Oncogene Proteins; Phenylurea Compounds; Protein Kinase Inhibitors; RNA, Messenger; Signal Transduction; Xenograft Model Antitumor Assays |
顯示於: | 腫瘤醫學研究所 |
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