Inhibition of CIP2A determines erlotinib-induced apoptosis in hepatocellular carcinoma
Journal
Biochemical Pharmacology
Journal Volume
85
Journal Issue
3
Pages
356-366
Date Issued
2013
Author(s)
Abstract
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.
Subjects
Apoptosis; CIP2A; Erlotinib; HCC; PP2A
SDGs
Other Subjects
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
Type
journal article