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

Oncogene volume 29, pages 6257–6266 (2010)Cite this article

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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 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.

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Abbreviations

HCC:

hepatocellular carcinoma

PP2A:

protein phosphatase 2A

CIP2A:

cancerous inhibitor of PP2A

PI3K:

phosphatidylinositol-3-kinase

PDK1:

phosphatidylinositol-3-kinase-dependent 1

PARP:

poly (ADP-ribose) polymerase

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

fetal bovine serum

i.p.:

intraperitoneal

s.c.:

subcutaneous

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Acknowledgements

Supported by NTUH98P03, NTUH98FTN21 from National Taiwan University Hospital and NSC97-2314-B-002-182, NSC98-2314-B-002-067-MY3, NSC98-3112-B-002-037 from the National Science Council, Taiwan.

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Authors and Affiliations

  1. Departments of Medical Research, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    K-F Chen, H-C Yu, T-H Liu & P-J Chen

  2. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    K-F Chen, H-C Yu, T-H Liu, P-J Chen & A-L Cheng

  3. Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    C-Y Liu

  4. School of Medicine, National Yang-Ming University, Taipei, Taiwan

    C-Y Liu

  5. Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan

    Y-C Lin

  6. Department of Chemistry, National Central University, Taoyuan, Taiwan

    D-R Hou

  7. Departments of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    A-L Cheng

  8. Departments of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    A-L Cheng

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Correspondence to A-L Cheng.

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Chen, KF., Liu, CY., Lin, YC. et al. CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells. Oncogene 29, 6257–6266 (2010). https://doi.org/10.1038/onc.2010.357

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