期刊
CANCER LETTERS
卷 284, 期 1, 页码 62-70出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2009.04.012
关键词
Adult T cell leukemia lymphoma; Heat shock protein 90; beta-catenin; Microarray
类别
资金
- High-Tech Research Center
- MEXT (Ministry of Education, Culture, Sports, Science and Technology, 2003-2007)
- University-Industry joint Research Project
The aim of this study is to evaluate the effect of heat shock protein 90 (Hsp90) inhibition, and to identify molecular pathways responsible for anti-proliferative effect on adult T cell leukemia/lymphoma (ATL) cells. For Hsp90 inhibition, we used geldanamycin derivates, 17-AAG (17-allylamino-17-demethoxygeldanamycin) and 17-DMAG (17-(dimethylaminoethylamino) 17-demethoxygeldanamycin) in this study. The inhibitory concentration (IC50) of 17-AAG in an ATL cell line, designated as TaY, and two HTLV-1 transformed cell lines (MT-2 and MT-4) was 300-700 nM, and that of 17-DMAG was 150-200 nM. Fresh ATL cells obtained from patients were more sensitive to both 17-AAG and 17-DMAG. Gene expression analysis of TaY cells revealed up-regulation of HSPA1A encoding Hsp70, a hallmark of Hsp90 inhibition. Genes regulating cell proliferation or anti-apoptosis (i.e. BCL2 and BIRC5), genes related to cytokines or chemokines (i.e. IL9 and CCL27), and notably TCF7L2, a down-stream effecter of P-catenin were remarkably down-regulated. Down-regulation of TCF7L2 mRNA was noted in the three cell lines and two patient specimens after Hsp90 inhibition. Hsp90 inhibitors dephosphorylate AKT, thereby, activate GSK-3 beta, which phosphorylates; beta-catenin for ubiquitination. This indicates the possibility that beta-catenin/TCF7L2 pathway plays an important role in Hsp90 inhibitor-induced cell death in ATL cells and HTLV-1 transformed cells. Our results have provided new insights into the complex molecular pharmacology of Hsp90 inhibitors, and suggest that Hsp90 inhibitors might be beneficial as anti-proliferative agents in treating ATL patients. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
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