國家衛生研究院 NHRI:Item 3990099045/6458
English  |  正體中文  |  简体中文  |  全文笔数/总笔数 : 12145/12927 (94%)
造访人次 : 909182      在线人数 : 809
RC Version 6.0 © Powered By DSPACE, MIT. Enhanced by NTU Library IR team.
搜寻范围 查询小技巧：
  • 您可在西文检索词汇前后加上"双引号"，以获取较精准的检索结果
  • 若欲以作者姓名搜寻，建议至进阶搜寻限定作者字段，可获得较完整数据
    •  进阶搜寻
    主页 ‧ 登入 ‧ 上传 ‧ 说明 ‧ 关于NHRI ‧ 管理 到手机版


    jsp.display-item.identifier=請使用永久網址來引用或連結此文件: http://ir.nhri.org.tw/handle/3990099045/6458


    题名: Involvement of autophagy in endogenous and NVP-AUY922-induced C-kit degradation in both imatinib-sensitive and -resistant gastrointestinal stromal tumor cells
    作者: Chen, LT;Hsueh, YS;Yen, CC;Shih, NY;Chiang, NJ;Li, CF
    贡献者: National Institute of Cancer Research
    摘要: Background: Heat shock protein 90 (HSP90) is a ubiquitously expressed chaperone involved in the post- translational maturation and stability of proteins. Inhibition of HSP90 leads to degradation of its client proteins, a process which is conceived to be mediated by the ubiquitin dependent proteasome machinery. Recent studies suggest that there are crosstalk between the two major protein degradation pathways within eukaryotic cells, the proteasome and autophagy pathways. However, the role of autophagy in degradation of HSP90 client proteins remains unclear. Methods and results: Our previous study has demonstrated that NVP-AUY922 (AUY922), a highly potent, non-geldanamycin HSP90 inhibitor, induced both growth inhibition and apoptosis in gastrointestinal stromal tumor (GIST) cells that express either an imatinib-sensitive, exon 13 mutated c-Kit (GIST882) or an imatinib-resistant, exon 11/17 double mutated c-Kit (GIST48). Signi?cant dose and time dependent reduction of both total and phosphorylated forms of c-Kit proteins in these cells were observed upon AUY922 treatment. This loss of c-Kit protein is due to accelerated c-Kit degradation as demonstrated by a shortened c-Kit half-life in the presence of AUY922 in cycloheximide treated GIST cells. AUY922-induced c-Kit reduction could be partially reversed by inhibiting either autophagy (by 3-MA, ba?lomycin-A or silencing beclin-1 expression by siRNA) or proteasome (by MG-132 or lactacystin) degradation pathways, and almost totally reversed by concomitant blocking of both degradation pathways. Interestingly, western blotting analysis showed that autophagy inhibitor or beclin-1 siRNA alone increased c-Kit protein level as compared with control GIST cells suggesting autophagy plays a role in c-Kit turnover even in the absence of AUY922. The involvement of autophagy in endogenous and AUY922-induced c-Kit protein turnover was further con?rmed by co-localization of c-Kit and autophagosome via immuno?uorescence staining. Conclusions: We demonstrated that AUY922 treatment induced down-regulation of c-Kit protein and apoptosis in both imatinib-sensitive and -resistant GIST cells. In addition to proteasome, autophagy mediated protein degradation may also play a pivotal role in both endogenous and HSP90 inhibitor induced c-Kit turn over in GIST. Our data support the potential use of AUY922 in treating TKI- refractory, c-Kit-expressing GIST and highlight a possible role for autophagy in HSP90 mediated client protein degradation.
    日期: 2012-03
    關聯: Annals of Oncology. 2012 Mar;23(Suppl. 1):28.
    Link to: http://dx.doi.org/10.1093/annonc/mds018
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0923-7534&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000303867100058
    显示于类别:[施能耀] 會議論文/會議摘要
    [陳立宗] 會議論文/會議摘要
    [姜乃榕] 會議論文/會議摘要

    文件中的档案:

    档案 描述 大小格式浏览次数
    ISI000303867100058.pdf51KbAdobe PDF651检视/开启


    在NHRI中所有的数据项都受到原著作权保护.

    TAIR相关文章

    DSpace Software Copyright © 2002-2004  MIT &  Hewlett-Packard  /   Enhanced by   NTU Library IR team Copyright ©   - 回馈