Abstract:
:Heat shock protein 90 (Hsp90) is widely overexpressed in cancer cells and necessary for maintenance of malignant phenotypes. Hsp90 inhibition induces tumor cell death through degradation of its client oncoproteins and has shown promises in preclinical studies. However, the mechanism by which Hsp90 inhibitors kill tumor cells is not well-understood. Biomarkers associated with differential sensitivity and resistance to Hsp90 inhibitors remain to be identified. In this study, we found that colorectal cancer cells containing inactivating mutations of FBW7, a tumor suppressor and E3 ubiquitin ligase, are intrinsically insensitive to Hsp90 inhibitors. The insensitive colorectal cancer cells lack degradation of Mcl-1, a prosurvival Bcl-2 family protein. Hsp90 inhibition promotes GSK3β-dependent phosphorylation of Mcl-1, which subsequently binds to FBW7 and undergoes ubiquitination and proteasomal degradation. Specifically blocking Mcl-1 phosphorylation by genetic knock-in abrogates its degradation and renders in vitro and in vivo resistance to Hsp90 inhibitors, which can be overcame by Mcl-1-selective small-molecule inhibitors. Collectively, our findings demonstrate a key role of GSK3β/FBW7-dependent Mcl-1 degradation in killing of colorectal cancer cells by Hsp90 inhibitors and suggest FBW7 mutational status as a biomarker for Hsp90-targeted therapy. Mol Cancer Ther; 16(9); 1979-88. ©2017 AACR.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Tong J,Tan S,Nikolovska-Coleska Z,Yu J,Zou F,Zhang Ldoi
10.1158/1535-7163.MCT-17-0032subject
Has Abstractpub_date
2017-09-01 00:00:00pages
1979-1988issue
9eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-17-0032journal_volume
16pub_type
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journal_title:Molecular cancer therapeutics
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2007-10-01 00:00:00
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pub_type: 杂志文章
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更新日期:2015-04-01 00:00:00
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journal_title:Molecular cancer therapeutics
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pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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更新日期:2004-02-01 00:00:00
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pub_type: 杂志文章,多中心研究
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更新日期:2020-02-01 00:00:00
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pub_type: 杂志文章,评审
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