CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells

• Published in: Oncogene Vol. 29; no. 47; pp. 6257 - 6266
• Main Authors: Chen, K-F, Liu, C-Y, Lin, Y-C, Yu, H-C, Liu, T-H, Hou, D-R, Chen, P-J, Cheng, A-L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.11.2010; Nature Publishing Group
• Subjects: 631/80/82/23; 631/92/609; 692/699/67/1504/1610; Ageing, cell death; AKT protein; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Autoantigens - genetics; Autoantigens - metabolism; Biological and medical sciences; Biomarkers, Tumor - deficiency; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Boronic Acids - pharmacology; Bortezomib; Cancer; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Biology; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chemotherapy; Down-Regulation - drug effects; Drug Resistance, Neoplasm; Drug therapy; Ectopic expression; Enzyme Activation - drug effects; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Gene Knockdown Techniques; Health aspects; Hepatocellular carcinoma; Hepatoma; Human Genetics; Humans; Internal Medicine; Liver cancer; Liver diseases; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Medicine; Medicine & Public Health; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Nude; Molecular and cellular biology; Oncology; original-article; Overexpression; Phosphatase; Phosphatases; Phosphoprotein phosphatase; Phosphoproteins - metabolism; Physiological aspects; Protein phosphatase; Protein Phosphatase 2 - metabolism; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pyrazines - pharmacology; RNA, Small Interfering - genetics; RNA-mediated interference; siRNA; Transcription, Genetic - drug effects; Tumors; Up-Regulation - drug effects; Xenograft Model Antitumor Assays; Taiwan; HCC; apoptosis; PP2A; proteasome inhibitor; CIP2A; bortezomib; Antineoplastic agent; Multicatalytic endopeptidase complex; Bortezomib; Enzyme; Akt protein kinase; Hepatic disease; Hepatocellular carcinoma; Malignant tumor; Carcinogenesis; Peptidases; Hydrolases; Digestive diseases; Inhibitor; Cancer; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.357

Previously, we reported that Akt inactivation determines the sensitivity of hepatocellular carcinoma (HCC) cells to bortezomib. In this study, we report that cancerous inhibitor of protein phosphatase 2A (CIP2A), a cellular inhibitor of protein phosphatase 2A (PP2A), mediates the apoptotic effect of bortezomib in HCC. Silencing PP2A by small interference RNA (siRNA) abolishes bortezomib-induced down-regulation of phospho-Akt and apoptosis. Bortezomib increases PP2A activity in sensitive HCC cells, including Sk-Hep1, Hep3B and Huh-7, but not in resistant PLC5 cells. Bortezomib down-regulates CIP2A in a dose- and time-dependent manner in all sensitive HCC cells, whereas no alterations in CIP2A were found in resistant PLC5 cells. Knockdown of CIP2A by siRNA restored bortezomib’s effects on apoptosis and PP2A activity in PLC5 cells. Moreover, over-expression of CIP2A up-regulated phospho-Akt and protected Sk-Hep1 cells from bortezomib-induced apoptosis. It is significant that, ectopic expression of CIP2A decreased Akt-related PP2A activity, whereas silencing CIP2A increased this activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells, furthermore, our in vivo data showed that bortezomib down-regulates CIP2A and up-regulates PP2A activity in Huh-7 tumors, but not in PLC5 tumors. In conclusion, inhibition of CIP2A determines the effects of bortezomib on apoptosis and PP2A-dependent Akt inactivation in HCC.