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
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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
収録刊行物
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- International Journal of Cancer
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International Journal of Cancer 120 (8), 1811-1820, 2007-01
Wiley-Liss, Inc.
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詳細情報 詳細情報について
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- CRID
- 1050011251830850944
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- NII論文ID
- 120001371787
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- NII書誌ID
- AA00680002
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- ISSN
- 00207136
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- HANDLE
- 20.500.12000/271
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- 本文言語コード
- en
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- 資料種別
- journal article
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- データソース種別
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- IRDB
- CiNii Articles
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