CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells
Journal
Oncogene
Journal Volume
29
Journal Issue
47
Pages
6257-6266
Date Issued
2010
Author(s)
Abstract
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 bortezomibs 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. ? 2010 Macmillan Publishers Limited All rights reserved.
SDGs
Other Subjects
bortezomib; phosphoprotein phosphatase 2A; small interfering RNA; animal cell; animal experiment; animal model; apoptosis; article; cancer cell culture; dose response; down regulation; drug effect; enzyme inhibition; gene expression; gene silencing; in vivo study; liver cell carcinoma; male; mouse; nonhuman; priority journal; timed drug release; upregulation; Animals; Apoptosis; Autoantigens; Boronic Acids; Carcinoma, Hepatocellular; Cell Line, Tumor; Down-Regulation; Drug Resistance, Neoplasm; Enzyme Activation; Gene Knockdown Techniques; Humans; Male; Membrane Proteins; Mice; Mice, Nude; Phosphoproteins; Protein Phosphatase 2; Proto-Oncogene Proteins c-akt; Pyrazines; RNA, Small Interfering; Transcription, Genetic; Tumor Markers, Biological; Up-Regulation; Xenograft Model Antitumor Assays
Type
journal article