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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
DC Field | Value | Language |
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dc.contributor.author | Jeon, Y K | - |
dc.contributor.author | Park, C H | - |
dc.contributor.author | Kim, K-Y | - |
dc.contributor.author | Li, Y C | - |
dc.contributor.author | Kim, J | - |
dc.contributor.author | Kim, Y A | - |
dc.contributor.author | Paik, J-H | - |
dc.contributor.author | Park, B-K | - |
dc.contributor.author | Kim, C-W | - |
dc.contributor.author | Kim, Y-N | - |
dc.date.accessioned | 2010-01-08T08:41:05Z | - |
dc.date.available | 2010-01-08T08:41:05Z | - |
dc.date.issued | 2007-09-05 | - |
dc.identifier.citation | J Pathol. 2007 Oct;213(2):170-9. | en |
dc.identifier.issn | 0022-3417 (Print) | - |
dc.identifier.issn | http://dx.doi.org/10.1002/path.2219 | - |
dc.identifier.issn | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17768706 | - |
dc.identifier.uri | https://hdl.handle.net/10371/29103 | - |
dc.description.abstract | NK/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.iso | en | en |
dc.publisher | Wiley-Blackwell | en |
dc.subject | 1-Phosphatidylinositol 3-Kinase/metabolism | en |
dc.subject | Antibiotics, Antineoplastic/*pharmacology | en |
dc.subject | Apoptosis/*drug effects | en |
dc.subject | Benzoquinones/*pharmacology | en |
dc.subject | Cell Survival | en |
dc.subject | Down-Regulation/drug effects | en |
dc.subject | Drug Evaluation, Preclinical | en |
dc.subject | HSP90 Heat-Shock Proteins/*antagonists & inhibitors | en |
dc.subject | Herpesvirus 4, Human/*isolation & purification | en |
dc.subject | Humans | en |
dc.subject | Lactams, Macrocyclic/*pharmacology | en |
dc.subject | Lymphoma, B-Cell/metabolism/pathology/virology | en |
dc.subject | Lymphoma, Extranodal NK-T-Cell/metabolism/*pathology | en |
dc.subject | Membrane Potential, Mitochondrial/physiology | en |
dc.subject | Oncogene Protein v-akt/metabolism | en |
dc.subject | Signal Transduction | en |
dc.subject | Tumor Cells, Cultured | en |
dc.title | The heat-shock protein 90 inhibitor, geldanamycin, induces apoptotic cell death in Epstein-Barr virus-positive NK/T-cell lymphoma by Akt down-regulation | en |
dc.type | Article | en |
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