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.
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-kappaB, 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.
Kawakami
Hirochika
H
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.
Tomita
Mariko
M
Okudaira
Taeko
T
Ishikawa
Chie
C
Matsuda
Takehiro
T
Tanaka
Yuetsu
Y
Nakazato
Tetsuro
T
Taira
Naoya
N
Ohshiro
Kazuiku
K
Mori
Naoki
N
D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000821:virology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C112765:tanespimycin; D051057:Proto-Oncogene Proteins c-akt