Bortezomib Sensitizes HCC Cells to CS-1008, an Antihuman Death Receptor 5 Antibody, through the Inhibition of CIP2A

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題名:	Bortezomib Sensitizes HCC Cells to CS-1008, an Antihuman Death Receptor 5 Antibody, through the Inhibition of CIP2A
作者:	Chen,KF;Yu,HC;Liu,CY;Chen,HJ;Chen,YC;Hou,DR;Chen,PJ;Cheng,AL
貢獻者:	化學學系
關鍵詞:	TRAIL-INDUCED APOPTOSIS;NF-KAPPA-B;LIGAND (TRAIL)-INDUCED APOPTOSIS;HEPATOCELLULAR-CARCINOMA CELLS;PROTEIN PHOSPHATASE 2A;PROTEASOME INHIBITORS;MEDIATED APOPTOSIS;UP-REGULATION;TUMOR-CELLS;GASTRIC-CANCER
日期:	2011
上傳時間:	2012-03-27 18:11:05 (UTC+8)
出版者:	國立中央大學
摘要:	Previously, we have shown that bortezomib overcame TRAIL resistance in hepatocellular carcinoma (HCC) cells via the inhibition of Akt. Here, we report that bortezomib sensitizes these TRAIL-resistant cells, including Huh-7, Hep3B, and Sk-Hep1, to CS-1008, a humanized agonistic antihuman death receptor 5 antibody. Cancerous inhibitor of protein phosphatase 2A (CIP2A) mediated the sensitizing effect of bortezomib to CS-1008 through inhibiting protein phosphatase 2A (PP2A) activity. Combination treatment of bortezomib and CS-1008 downregulated CIP2A in a concentration-and time-dependent manner, and increased PP2A activity in HCC cells. Importantly, ectopic expression of CIP2A decreased Akt-related PP2A activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells. Moreover, silencing CIP2A by short interfering RNA enhanced CS-1008-induced apoptosis in HCC cells and ectopic expression of CIP2A in HCC cells abolished CS-1008-induced apoptosis, indicating that CIP2A plays an important role in the sensitizing effect of bortezomib to CS-1008. Finally, our in vivo data showed that CS-1008 and bortezomib combination treatment decreased tumor growth significantly. In conclusion, bortezomib sensitized HCC cells to CS-1008 through the inhibition of CIP2A. Mol Cancer Ther; 10(5); 892-901. (C) 2011 AACR.
關聯:	MOLECULAR CANCER THERAPEUTICS
顯示於類別:	[化學學系] 期刊論文

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