S-Space College of Medicine/School of Medicine (의과대학/대학원) Program in Cancer Biology (협동과정-종양생물학전공) Journal Papers (저널논문_협동과정-종양생물학전공)
The heat-shock protein 90 inhibitor, geldanamycin, induces apoptotic cell death in Epstein-Barr virus-positive NK/T-cell lymphoma by Akt down-regulation
- Jeon, Y K; Park, C H; Kim, K-Y; Li, Y C; Kim, J; Kim, Y A; Paik, J-H; Park, B-K; Kim, C-W; Kim, Y-N
- Issue Date
- J Pathol. 2007 Oct;213(2):170-9.
- 1-Phosphatidylinositol 3-Kinase/metabolism; Antibiotics, Antineoplastic/*pharmacology; Apoptosis/*drug effects; Benzoquinones/*pharmacology; Cell Survival; Down-Regulation/drug effects; Drug Evaluation, Preclinical; HSP90 Heat-Shock Proteins/*antagonists & inhibitors; Herpesvirus 4, Human/*isolation & purification; Humans; Lactams, Macrocyclic/*pharmacology; Lymphoma, B-Cell/metabolism/pathology/virology; Lymphoma, Extranodal NK-T-Cell/metabolism/*pathology; Membrane Potential, Mitochondrial/physiology; Oncogene Protein v-akt/metabolism; Signal Transduction; Tumor Cells, Cultured
- 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.
- 0022-3417 (Print)
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