Anti-proliferative activity of heat shock protein (Hsp) 90 inhibitors via b-catenin/TCF7L2 pathway in adult T cell leukemia cells

• Published in: Cancer letters 2009-10, Vol.284 (1), p.62-70
• Main Authors: Kurashina, Ryosuke, Ohyashiki, Junko H, Kobayashi, Chiaki, Hamamura, Ryoko, Zhang, Yu, Hirano, Toshihiko, Ohyashiki, Kazuma
• Format: Article
• Language: English
• Subjects: Human T-lymphotropic virus 1
• ISSN: 0304-3835
• DOI: 10.1016/j.canlet.2009.04.012

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 (IC sub(50)) 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 b-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-3b, which phosphorylates b-catenin for ubiquitination. This indicates the possibility that b-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.