國家衛生研究院 NHRI:Item 3990099045/6458
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    題名: 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
    貢獻者: 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
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