國家衛生研究院 NHRI:Item 3990099045/4389
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    题名: Down-regulation of phospho-Akt is a major molecular determinant of bortezomib-induced apoptosis in hepatocellular carcinoma cells
    作者: Chen, KF;Yeh, PY;Yeh, KH;Lu, YS;Huang, SY;Cheng, AL
    贡献者: National Institute of Cancer Research
    摘要: 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: Hub-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 G(2)-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-kappa 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.
    日期: 2008-08
    關聯: Cancer Research. 2008 Aug;68(16):6698-6707.
    Link to: http://dx.doi.org/10.1158/0008-5472.can-08-0257
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0008-5472&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000258548200027
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=53049087511
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