title: Inhibition of CIP2A determines erlotinib-induced apoptosis in hepatocellular carcinoma.
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 HA59T 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 HA59T cells. Combining Akt inhibitor MK-2206 with erlotinib restored the sensitivity of HA59T 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.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. gane-mai@yahoo.com.tw
authors.forename: Hui-Chuan
authors.initials: HC
authors.lastname: Yu
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Chen
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Chang
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D000069347:Erlotinib Hydrochloride; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering
chemical_list: D001324:Autoantigens; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D000069347:Erlotinib Hydrochloride; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2