2024-03-28T22:16:06Z
https://u-ryukyu.repo.nii.ac.jp/oai
oai:u-ryukyu.repo.nii.ac.jp:02000889
2023-08-03T05:33:02Z
1642838163960:1642838338003
1642838403551:1642838407795
Inhibition of heat shock protein-90 modulates multiple functions required for survival of human T-cell leukemia virus type I-infected T-cell lines and adult T-cell leukemia cells
Kawakami, Hirochika
Tomita, Mariko
Okudaira, Taeko
Chie, Ishikawa
Matsuda, Takehiro
Tanaka, Yuetsu
Nakazato, Tetsuro
Taira, Naoya
Ohshiro, Kazuiku
Mori, Naoki
ATL
HTLV-I
17-AAG
Hsp90
client protein
The molecular chaperone Hsp90 is involved in the stabilization and conformational maturation of many signaling proteins that are deregulated in cancers. The geldanamycin derivative 17-AAG is currently tested in clinical trials and known to inhibit the function of Hsp90 and promote the proteasomal degradation of its misfolded client proteins. ATL is a fatal malignancy of T lymphocytes caused by HTLV-I infection and remains incurable. Since Hsp90 is overexpressed in HTLV-I-infected T-cell lines and primary ATL cells, we analyzed the effects of 17-AAG on cell survival, apoptosis and expression of signal transduction proteins. HTLV-I-infected T-cell lines and primary ATL cells were significantly more sensitive to 17-AAG in cell survival assays than normal PBMCs. 17-AAG induced the inhibition of cell cycle and apoptosis. These effects could be mediated by inactivation of NF-B, AP-1 and PI3K/Akt pathways, as well as reduction of expression of proteins involved in the G1-S cell cycle transition and apoptosis. Proteasome inhibition interfered with 17-AAG-mediated signaling proteins depletion. Collectively, our results indicate that 17-AAG suppresses ATL cell survival through, at least in part, destabilization of several client proteins and suggest that 17-AAG is a potentially useful chemotherapeutic agent for ATL.
論文
http://purl.org/coar/resource_type/c_6501
Wiley-Liss, Inc.
2007-01
AM
http://hdl.handle.net/20.500.12000/271
00207136
AA00680002
International Journal of Cancer
8
120
1820
1811
eng
10.1002/ijc.22403
open access
Copyright (c) 2007 Wiley-Liss, Inc