{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T10:22:45Z","timestamp":1762078965194,"version":"build-2065373602"},"reference-count":47,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2007,9,3]],"date-time":"2007-09-03T00:00:00Z","timestamp":1188777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2007,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>NK\/T\u2010cell lymphoma (NKTL) is strongly associated with latent Epstein\u2013Barr virus (EBV) infection. Recently, latent membrane protein 1 (LMP1), an EBV oncoprotein, was reported to activate the phosphatidylinositol\u20103 kinase (PI3K)\/Akt pathway for cell survival. Because geldanamycin (GA) and its derivative, 17\u2010allylamino\u201017\u2010demethoxygeldanamycin (17\u2010AAG), exhibit anti\u2010tumour activity by degrading HSP90 client proteins, including Akt, we investigated the effect of GA and 17\u2010AAG on the survival of NKTL cell lines. EBV\u2010positive NKTL cell lines, Hank\u20101 and NK\u2010YS, and an EBV\u2010negative NK leukaemia cell line, NK\u2010L, were treated with PI3K and Akt inhibitors, GA, and 17\u2010AAG, and were subjected to apoptosis and cell viability assays, and immunoblot analysis. EBV\u2010positive B\u2010lymphoblastoid cell lines IM9 and LMP1\u2010transfected IM9 (IM9\u2010LMP1) were also included. Hank\u20101 and NK\u2010YS cell viability was compromised and apoptosis was induced by LY294002 (PI3K inhibitor) or Akt inhibitor II. GA or 17\u2010AAG administration resulted in the apoptosis of NKTL cells, accompanied by Akt and pAkt down\u2010regulation, caspase 3 activation, and mitochondrial membrane potential disruption. The intrinsic level of pAkt was higher in EBV\u2010positive NKTL cells than in EBV\u2010negative NK\u2010L, and GA or 17\u2010AAG decreased the viability of NKTL cells more efficiently than NK\u2010L. Moreover, IM9\u2010LMP1 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\u2010neoplastic counterparts for comparison. In conclusion, this study suggests that the PI3K\/Akt pathway is frequently activated in EBV\u2010positive NKTL and that therapeutic modalities based on targeting the PI3K\/Akt pathway with HSP90 inhibitors could be useful for achieving NKTL control. Copyright \u00a9 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.2219","type":"journal-article","created":{"date-parts":[[2007,9,3]],"date-time":"2007-09-03T11:46:57Z","timestamp":1188820017000},"page":"170-179","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["The heat\u2010shock protein 90 inhibitor, geldanamycin, induces apoptotic cell death in Epstein\u2013Barr virus\u2010positive NK\/T\u2010cell lymphoma by Akt down\u2010regulation"],"prefix":"10.1002","volume":"213","author":[{"given":"YK","family":"Jeon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"CH","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K\u2010Y","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"YC","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"YA","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u2010H","family":"Paik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B\u2010K","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u2010W","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y\u2010N","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2007,9,20]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc839"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2402824"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207115"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02369"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.MP.0000067423.83712.74"},{"key":"e_1_2_6_7_2","first-page":"2194","article-title":"Role of phosphatidylinositol 3\u2010kinase\u2013Akt pathway in nucleophosmin\/anaplastic lymphoma kinase\u2010mediated lymphomatogenesis","volume":"61","author":"Slupianek A","year":"2001","journal-title":"Cancer Res"},{"key":"e_1_2_6_8_2","first-page":"6763","article-title":"The phosphatidylinositol 3\u2010kinase\/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine\u2010dependent survival and proliferative response","volume":"60","author":"Tu Y","year":"2000","journal-title":"Cancer Res"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-1857"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1080\/10428190500159944"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4914(02)02316-X"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01913"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(03)00029-1"},{"key":"e_1_2_6_14_2","first-page":"204","volume-title":"World Health Organization Classification of Tumours. 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