期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 23, 期 9, 页码 2010-2013出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201604807
关键词
biological activity; cancer; CRISPR; heat shock protein 90; phenotype
资金
- US National Institute of Health [NCI R01CA137873]
- Australian National Health and Medical Research Council (NHMRC) [GNT1043561]
- UNSW
- NHMRC
- Endeavour program
The phenotypes produced when cells are treated with the heat shock protein 90 (Hsp90) inhibitors AUY922 or 17-AAG (classical inhibitors) are different to those produced when cells are knocked down with Hsp90 alpha. Pull-down assays using classical inhibitors suggest that these molecules bind to multiple targets other than Hsp90. Classical inhibitors also induce similar protein markers as other anti-cancer therapies cisplatin and borte-zomib that do not target Hsp90. Together these data suggest that AUY922 and 17-AAG acts on multiple targets and likely kills cells through multiple mechanisms. Comparing these classical inhibitors to the effects seen when treating cells with C-terminal Hsp90 modulators reveals that C-terminal modulators effectively bind to Hsp90, and induce phenotypic markers consistent with the Hsp90a CRISPR knockdown data. Our findings challenge the current interpretation of Hsp90 inhibitors and suggest that a large body of literature that describes the Hsp90 phenotype and inhibitors is re-examined in this context.
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