Inhibition of CIP2A determines erlotinib-induced apoptosis in hepatocellular carcinoma

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• 作者：Hui-Chuan Yu^a ; ^b ; ¹ ; ^{gane-mai@yahoo.com.tw} ; Hui-Ju Chen^a ; ^b ; ¹ ; ^{hjchen23@hotmail.com} ; Ya-Ling Chang^a ; ^b ; ^f ; ¹ ; ^{smimichung@yahoo.com.tw} ; Chun-Yu Liu^d ; ^e ; ^g ; ^{liuchunyu_tw@yahoo.com.tw} ; Chung-Wai Shiau^e ; ^{cwshiau@ym.edu.tw} ; Ann-Lii Cheng^b ; ^c ; ^{alcheng@ntu.edu.tw} ; Kuen-Feng Chen^a ; ^b ; ^{kfchen1970@ntu.edu.tw}
• 关键词：HCC ; hepatocellular carcinoma ; PP2A ; protein phosphatase 2A ; CIP2A ; cancerous inhibitor of PP2A ; PI3 K ; phosphatidylinositol-3-kinase ; PDK1 ; phosphatidylinositol-3-kinase dependent 1 ; PARP ; poly (ADP-ribose) polymerase ; DMEM ; Dulbecco's modified Eagle's m
• 刊名：Biochemical Pharmacology
• 出版年：2013
• 出版时间：1 February, 2013
• 年：2013
• 卷：85
• 期：3
• 页码：356-366
• 全文大小：1687 K

文摘

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.