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

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.

Heat Shock Protein 90 Inhibitor Induces Apoptosis and Attenuates Activation of Hepatic Stellate Cells

“…The concentration of 17AAG used in this study was 10 M, which is relatively higher compared with those used in other studies (up to 2 M) (Jeon et al, 2007;Al Shaer et al, 2008;Meyer et al, 2008), although this is consistent with the relative resistance of HSCs to apoptotic stimuli (Novo et al, 2006;Hannivoort et al, 2008). We then attempted to sensitize HSCs to 17AAG-induced apoptosis.…”

Nuclear Transport of Epstein-Barr Virus DNA Polymerase Is Dependent on the BMRF1 Polymerase Processivity Factor and Molecular Chaperone Hsp90

“…Sun et al previously reported that Hsp90 inhibitors decreased expression of EBNA1 in EBV-infected cells, retarding the growth of EBV latently infected malignant cells via an EBNA1-dependent mechanism (43). Jeon et al described geldanamycin induction of apoptotic cell death in Epstein-Barr virus-positive NK/T-cell lymphoma cells by Akt downregulation (44). It is possible that inhibition of EBV DNA replication by the Hsp90 inhibitor may be due to effects not only on EBV DNA polymerase but also on other essential factors.…”

Natural Killer Cell Leukemia: Diagnosis, Pathogenesis and Treatment

“…The EBV oncoprotein LMP1 reportedly activates the phosphatidylinositol-3 kinase (PI3K)/Akt pathway to induce cell survival (Jeon, 2007). The intrinsic level of pAkt was higher in EBV-positive NK cells than in EBV-negative NK cells.…”