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The heat-shock protein 90 inhibitor, geldanamycin, induces apoptotic cell death in Epstein-Barr virus-positive NK/T-cell lymphoma by Akt down-regulation

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dc.contributor.authorJeon, Y K-
dc.contributor.authorPark, C H-
dc.contributor.authorKim, K-Y-
dc.contributor.authorLi, Y C-
dc.contributor.authorKim, J-
dc.contributor.authorKim, Y A-
dc.contributor.authorPaik, J-H-
dc.contributor.authorPark, B-K-
dc.contributor.authorKim, C-W-
dc.contributor.authorKim, Y-N-
dc.date.accessioned2010-01-08T08:41:05Z-
dc.date.available2010-01-08T08:41:05Z-
dc.date.issued2007-09-05-
dc.identifier.citationJ Pathol. 2007 Oct;213(2):170-9.en
dc.identifier.issn0022-3417 (Print)-
dc.identifier.issnhttp://dx.doi.org/10.1002/path.2219-
dc.identifier.issnhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17768706-
dc.identifier.urihttps://hdl.handle.net/10371/29103-
dc.description.abstractNK/T-cell lymphoma (NKTL) is strongly associated with latent Epstein-Barr virus (EBV) infection. Recently, latent membrane protein 1 (LMP1), an EBV oncoprotein, was reported to activate the phosphatidylinositol-3 kinase (PI3K)/Akt pathway for cell survival. Because geldanamycin (GA) and its derivative, 17-allylamino-17-demethoxygeldanamycin (17-AAG), exhibit anti-tumour activity by degrading HSP90 client proteins, including Akt, we investigated the effect of GA and 17-AAG on the survival of NKTL cell lines. EBV-positive NKTL cell lines, Hank-1 and NK-YS, and an EBV-negative NK leukaemia cell line, NK-L, were treated with PI3K and Akt inhibitors, GA, and 17-AAG, and were subjected to apoptosis and cell viability assays, and immunoblot analysis. EBV-positive B-lymphoblastoid cell lines IM9 and LMP1-transfected IM9 (IM9-LMP1) were also included. Hank-1 and NK-YS cell viability was compromised and apoptosis was induced by LY294002 (PI3K inhibitor) or Akt inhibitor II. GA or 17-AAG administration resulted in the apoptosis of NKTL cells, accompanied by Akt and pAkt down-regulation, caspase 3 activation, and mitochondrial membrane potential disruption. The intrinsic level of pAkt was higher in EBV-positive NKTL cells than in EBV-negative NK-L, and GA or 17-AAG decreased the viability of NKTL cells more efficiently than NK-L. Moreover, IM9-LMP1 was more sensitive to Akt inhibitor II or HSP90 inhibitors than IM9. Importantly, GA showed little effect on the viability of normal peripheral NK cells as non-neoplastic counterparts for comparison. In conclusion, this study suggests that the PI3K/Akt pathway is frequently activated in EBV-positive NKTL and that therapeutic modalities based on targeting the PI3K/Akt pathway with HSP90 inhibitors could be useful for achieving NKTL control.en
dc.language.isoenen
dc.publisherWiley-Blackwellen
dc.subject1-Phosphatidylinositol 3-Kinase/metabolismen
dc.subjectAntibiotics, Antineoplastic/*pharmacologyen
dc.subjectApoptosis/*drug effectsen
dc.subjectBenzoquinones/*pharmacologyen
dc.subjectCell Survivalen
dc.subjectDown-Regulation/drug effectsen
dc.subjectDrug Evaluation, Preclinicalen
dc.subjectHSP90 Heat-Shock Proteins/*antagonists & inhibitorsen
dc.subjectHerpesvirus 4, Human/*isolation & purificationen
dc.subjectHumansen
dc.subjectLactams, Macrocyclic/*pharmacologyen
dc.subjectLymphoma, B-Cell/metabolism/pathology/virologyen
dc.subjectLymphoma, Extranodal NK-T-Cell/metabolism/*pathologyen
dc.subjectMembrane Potential, Mitochondrial/physiologyen
dc.subjectOncogene Protein v-akt/metabolismen
dc.subjectSignal Transductionen
dc.subjectTumor Cells, Cultureden
dc.titleThe heat-shock protein 90 inhibitor, geldanamycin, induces apoptotic cell death in Epstein-Barr virus-positive NK/T-cell lymphoma by Akt down-regulationen
dc.typeArticleen
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College of Medicine/School of Medicine (의과대학/대학원)Program in Cancer Biology (협동과정-종양생물학전공)Journal Papers (저널논문_협동과정-종양생물학전공)
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