The heat-shock protein 90 inhibitor, geldanamycin, induces apoptotic cell death in Epstein-Barr virus-positive NK/T-cell lymphoma by Akt down-regulation
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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DOI：
10.1002/path.2219
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发表时间：
2007-10-01
影响因子：
7.3
通讯作者：
Kim, Y-N
中科院分区：
文献类型：
--
作者：
Jeon, Y. K.;Park, C. H.;Kim, Y-N
NK/T细胞淋巴瘤(NKTL)与EB病毒(EBV)潜伏感染密切相关。潜伏膜蛋白1(LMP1)是一种EBV癌蛋白，最近被报道激活磷脂酰肌醇-3激酶(Pl3K)/Akt信号通路，促进细胞存活。由于格尔达霉素(GA)及其衍生物17-烯丙氨基-17-去甲氧基格尔达霉素(17-AAG)通过降解包括Akt在内的HSP90客户蛋白而显示出抗肿瘤活性，因此我们研究了GA和17-AAG对NKTL细胞存活的影响。用PI3K和AKT抑制剂、GA和17-AAG处理EB病毒阳性的NKTL细胞株HANK-1和NK-YS以及EB病毒阴性的NK白血病细胞株NK-L，并进行细胞凋亡率、细胞存活率和免疫印迹分析。EBV阳性的B淋巴母细胞系IM9和转导LMP1的IM9(IM9-LMP1)也包括在内。LY294002(PI3K抑制剂)或Akt抑制剂II可诱导NKTL细胞凋亡，同时伴有Akt和Akt蛋白表达下调，caspase3激活，线粒体膜电位紊乱。EBV阳性的NKTL细胞中PAKT的内源性水平高于EBV阴性的NK-L细胞，且GA或17-AAG对NKTL细胞活力的抑制作用比NK-L更有效。此外，IM9-LMP1对Akt抑制剂11或HSP90抑制剂的敏感性高于IM9。重要的是，与非肿瘤性NK细胞相比，GA对正常外周血NK细胞的活性几乎没有影响。总之，本研究提示，在EBV阳性的NKTL中，PI3K/Akt通路经常被激活，基于HSP90抑制剂靶向PI3K/Akt通路的治疗方法可能有助于实现NKTL的控制。版权所有(C)2007年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
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 (Pl3K)/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 11 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 (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.