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Down-regulation of Phospho-Akt Is a Major Molecular Determinant of Bortezomib-Induced Apoptosis in Hepatocellular Carcinoma Cells

Departments of ¹ Medical Research and ² Oncology, ³ Cancer Research Center, ⁴ Graduate Institute of Clinical Medicine, and ⁵ Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine; and ⁶ Institute of Cancer Research, National Health Research Institute, Taipei, Taiwan

Requests for reprints: Ann-Lii Cheng, Departments of Internal Medicine and Oncology, National Taiwan University Hospital, No 7, Chung-Shan South Road, Taipei, Taiwan. Phone: 886-2-23123456, ext. 7251; Fax: 886-2-23711174; E-mail: alcheng{at}ntu.edu.tw

Key Words: Proteasome inhibitor • Akt • Apoptosis • Cancer • Molecular Targeted Therapy

Bortezomib, a proteasome inhibitor, has been clinically approved for the treatment of myeloma and lymphoma. Here, we report a differential effect of bortezomib on apoptosis in four hepatocellular carcinoma (HCC) cell lines and identify the major molecular event that determines sensitivity. Although bortezomib inhibited proteasome activity to a similar extent in all HCC cell lines, it showed differential effects on their viability: Huh-7 (IC₅₀ 196 nmol/L), Sk-Hep1 (IC₅₀ 180 nmol/L), Hep3B (IC₅₀ 112 nmol/L), and resistant PLC5 (IC₅₀ >1,000 nmol/L). Bortezomib caused cell cycle arrest at G₂-M phase in all HCC cells tested whereas apoptotic induction was found only in sensitive cells but not in PLC5 cells. No significant bortezomib-induced NF-B changes were noted in Huh-7 and PLC5. Bortezomib down-regulated phospho-Akt (P-Akt) in a dose- and time-dependent manner in all sensitive HCC cells whereas no alterations of P-Akt were found in PLC5. Down-regulation of Akt1 by small interference RNA overcame the apoptotic resistance to bortezomib in PLC5 cells, but a constitutively activated Akt1 protected Huh-7 cells from bortezomib-induced apoptosis. Furthermore, bortezomib showed suppression of tumor growth with down-regulation of P-Akt in Huh-7 tumors but not in PLC5 tumors. Down-regulation of P-Akt represents a major molecular event of bortezomib-induced apoptosis in HCC cell lines and may be a biomarker for predicting clinical response to HCC treatment. Targeting Akt signaling overcomes drug resistance to bortezomib in HCC cells, which provides a new approach for the combinational therapy of HCC. [Cancer Res 2008;68(16):6698–707]

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