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

• Published in: The Journal of pathology 2007-10, Vol.213 (2), p.170-179
• Main Authors: Jeon, YK, Park, CH, Kim, K.Y, Li, YC, Kim, J, Kim, YA, Paik, J.H, Park, B.K, Kim, C.W, Kim, Y.N
• Format: Article
• Language: English
• Subjects: Akt; Antibiotics, Antineoplastic - pharmacology; apoptosis; Apoptosis - drug effects; Benzoquinones - pharmacology; Biological and medical sciences; Cell Survival; Down-Regulation - drug effects; Drug Evaluation, Preclinical; Epstein-Barr virus; geldanamycin; Herpesvirus 4, Human - isolation & purification; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 inhibitor; Humans; Investigative techniques, diagnostic techniques (general aspects); Lactams, Macrocyclic - pharmacology; LMP1; Lymphoma, B-Cell - metabolism; Lymphoma, B-Cell - pathology; Lymphoma, B-Cell - virology; Lymphoma, Extranodal NK-T-Cell - metabolism; Lymphoma, Extranodal NK-T-Cell - pathology; Medical sciences; Membrane Potential, Mitochondrial - physiology; NK/T-cell lymphoma; Oncogene Protein v-akt - metabolism; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phosphatidylinositol 3-Kinases - metabolism; PI3-kinase; Signal Transduction; Tumor Cells, Cultured
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2219

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. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.