https://scholars.lib.ntu.edu.tw/handle/123456789/580219
標題: | Inhibition of CIP2A determines erlotinib-induced apoptosis in hepatocellular carcinoma | 作者: | Yu H.-C. Chen H.-J. Chang Y.-L. Liu C.-Y. Shiau C.-W. ANN-LII CHENG Chen K.-F. |
關鍵字: | Apoptosis; CIP2A; Erlotinib; HCC; PP2A | 公開日期: | 2013 | 卷: | 85 | 期: | 3 | 起(迄)頁: | 356-366 | 來源出版物: | Biochemical Pharmacology | 摘要: | Erlotinib is a small-molecular inhibitor of epidermal growth factor receptor (EGFR). Here, we identify that cancerous inhibitor of protein phosphatase 2A (CIP2A) is a major determinant mediating erlotinib-induced apoptosis in hepatocellular carcinoma (HCC). Erlotinib showed differential effects on apoptosis in 4 human HCC cell lines. Erlotinib induced significant apoptosis in Hep3B and PLC5 cell lines; however, Huh-7 and HA59 T cell lines showed resistance to erlotinib-induced apoptosis at all tested doses. Down-regulation of CIP2A, a cellular inhibitor of protein phosphatase 2A (PP2A), mediated the apoptotic effect of erlotinib in HCC. Erlotinib inhibited CIP2A in a dose- and time-dependent manner in all sensitive HCC cells whereas no alterations in CIP2A were found in resistant cells. Overexpression of CIP2A upregulated phospho-Akt and protected Hep3B cells from erlotinib-induced apoptosis. In addition, silencing CIP2A by siRNA restored the effects of erlotinib in Huh-7 cells. Moreover, adding okadaic acid, a PP2A inhibitor, abolished the effects of erlotinib on apoptosis in Hep3B cells; and forskolin, a PP2A agonist enhanced the effect of erlotinib in resistant HA59 T cells. Combining Akt inhibitor MK-2206 with erlotinib restored the sensitivity of HA59 T cells to erlotinib. Furthermore, in vivo xenograft data showed that erlotinib inhibited the growth of PLC5 tumor but had no effect on Huh-7 tumor. Erlotinib downregulated CIP2A and upregulated PP2A activity in PLC5 tumors, but not in Huh-7 tumors. In conclusion, inhibition of CIP2A determines the effects of erlotinib on apoptosis in HCC. CIP2A may be useful as a therapeutic biomarker for predicting clinical response to erlotinib in HCC treatment. ? 2012 Elsevier Inc. All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84872682401&doi=10.1016%2fj.bcp.2012.11.009&partnerID=40&md5=b82ccae4a29c43e7d0c48a9530c15e73 https://scholars.lib.ntu.edu.tw/handle/123456789/580219 |
DOI: | 10.1016/j.bcp.2012.11.009 | SDG/關鍵字: | 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one; erlotinib; forskolin; okadaic acid; phosphoprotein phosphatase 2A; protein kinase B; small interfering RNA; animal experiment; animal model; apoptosis; article; cancer growth; controlled study; down regulation; drug inhibition; gene overexpression; gene silencing; human cell culture; immunoprecipitation; liver cell carcinoma; male; mouse; nonhuman; priority journal; sensitivity analysis; tumor xenograft; upregulation; Western blotting; Animals; Apoptosis; Autoantigens; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Down-Regulation; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Liver Neoplasms; Male; Membrane Proteins; Mice; Mice, Nude; Neoplasms, Experimental; Protein Kinase Inhibitors; Protein Phosphatase 2; Proto-Oncogene Proteins c-akt; Quinazolines; RNA, Small Interfering |
顯示於: | 醫學系 |
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