國家衛生研究院 NHRI:Item 3990099045/2738
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    題名: Tamoxifen accelerates proteasomal degradation of O-6-methylguanine DNA methyltransferase in human cancer cells
    作者: Kuo, CC;Liu, JF;Shiah, HS;Ma, LC;Chang, JY
    貢獻者: National Institute of Cancer Research
    摘要: Tamoxifen, a synthetic triphenyl-ethylene compound, is a member of a class of anticancer drugs known as selective estrogen receptor modulators. It may block tumor growth by mimicking estrogen and binding to the estrogen receptors, preventing cancerous growth. Clinical studies have demonstrated that a combination chemo/hormonal therapy regimen with tamoxifen and O-6 -alkylating drugs increased the tumor response rate in cancer patients. The mechanism of action of this combined regimen remains undefined. In this study, we demonstrated that treatment of human colorectal HT-29 carcinoma cells with tamoxifen decreased the repair activity and expression level of O-6 -methylguanine DNA methyltransferase (MGMT) protein in a concentration- and time-dependent manner. This inhibition was also shown in other malignant human cells, regardless of their estrogen receptor status. Furthermore, MGMT inactivation by tamoxifen was associated with a significantly increased susceptibility of cells to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). No alteration in MGMT mRNA levels was observed in tamoxifen-treated cells. The half-life of MGMT protein was markedly decreased in the presence of tamoxifen. Ta moxifen- induced MGMT degradation could be blocked by MG-132, a proteasome inhibitor. An increased level of ubiquitinated MGMT protein was found after tamoxifen treatment. We conclude that tamoxifen decreased the MGMT protein level by accelerating protein degradation through the ubiquitin-dependent proteasomal pathway. These findings provide a strong rationale for combined chemo/hormonal therapy with tamoxifen and BCNU in the treatment of human cancers. (c) 2007 Wiley-Liss, Inc.
    關鍵詞: Oncology
    日期: 2007-11-15
    關聯: International Journal of Cancer. 2007 Nov;121(10):2293-2300.
    Link to: http://dx.doi.org/10.1002/ijc.22927
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0020-7136&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000250245100024
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=35348920182
    顯示於類別:[張俊彥] 期刊論文
    [夏和雄(1996-2012)] 期刊論文
    [郭靜娟] 期刊論文

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