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Title :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
Authors :Kawakami, Hirochika
Tomita, Mariko
Okudaira, Taeko
Chie, Ishikawa
Matsuda, Takehiro
Tanaka, Yuetsu
Nakazato, Tetsuro
Taira, Naoya
Ohshiro, Kazuiku
Mori, Naoki
Issue Date :Jan-2007
Abstract :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.
Type Local :雑誌掲載論文
ISSN :00207136
Publisher :Wiley-Liss, Inc.
URI :http://hdl.handle.net/20.500.12000/271
Citation :International Journal of Cancer Vol.120 no.8 p.1811 -1820
Appears in Collections:Peer-reviewed Journal Articles (Faculty of Medicine)

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