Anti-proliferative activity of heat shock protein (Hsp) 90 inhibitors via beta-catenin/TCF7L2 pathway in adult T cell leukemia cells.
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(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 150-200nM. 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 beta-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-3beta, 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.
Kurashina
Ryosuke
R
First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.
Ohyashiki
Junko H
JH
Kobayashi
Chiaki
C
Hamamura
Ryoko
R
Zhang
Yu
Y
Hirano
Toshihiko
T
Ohyashiki
Kazuma
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D051820:TCF Transcription Factors / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin / Q000378:metabolism*
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C112765:tanespimycin