國家衛生研究院 NHRI:Item 3990099045/6906
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    题名: Heat shock protein 90 inhibition downregulates c-Kit expression in gist cells through diminishing transcription and enhancing protein degradation via both autophagy and proteasome pathways
    作者: Hsueh, Y;Yen, C;Shih, N;Chiang, N;Li, C;Chen, L
    贡献者: National Institute of Cancer Research
    摘要: Background: Gastrointestinal stromal tumor (GIST) is a mutant oncoprotein c-Kit droved cancer. Patients suffered drug resistance after prolonged standard treatment of tyrosine kinase inhibitor (TKI), imatinib mesylate (IM). Inhibition of heat-shock protein 90 (Hsp90), a chaperone responsible for protein maturation and stability, causing its client proteins degradation, as c-Kit, is a developing therapy for cancer. However, the mechanisms of Hsp90 inhibition-induced c-Kit downregulation in post-translational and transcriptional levels have rarely been investigated. Methods and results: Our data showed that NVP-AUY922 (AUY922), a new class of Hsp90 inhibitor, inhibited the growth of GIST882 and GIST48 cells with mutant c-Kit protein expression that was accompanied with reduction of both total and phosphor-c-Kit protein and induction of apoptosis. Pharmacological inhibition on either autophagy or proteasome degradation pathway could partially reverse endogenous c-Kit turnover and AUY922-induced c-Kit reduction. These findings were further confirmed by the co-localization of c-Kit with either LC-3B or acridine orange-labeled autophagosome in confocal microscopy, and delay of c-Kit degradation by silencing autophagosome essential Beclin-1 protein. In addition, AUY922 could also reduce c-Kit mRNA without affecting its degradation. Our preliminary data showed that activities and nuclear levels of several transcription factors in GIST cells were diminished after AUY922 treatment. DNA affinity precipitation assay and chromatin immunoprecipitation (ChIP) will be performed to validate the binding of the candidate transcript factors on the c-Kit promoter. Conclusions: This is the first report showing the involvement of autophagy in endogenous as well as Hsp90 inhibitor-induced c-Kit degradation. Moreover, AUY922 treatment resulted in downregulation of c-Kit through protein degradation and transcriptional mRNA regulation in GIST cells. These findings address the mechanisms of AUY922 on c-Kit protein downregulation and highlight the potential use of AUY922 in TKI-refractory, c-Kit-expressing GIST
    日期: 2012-09
    關聯: Annals of Oncology. 2012 Sep;23(Suppl. 9):538.
    Link to: http://dx.doi.org/10.1093/annonc/mds417
    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:000309409003036
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