{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:58:28Z","timestamp":1792627108665,"version":"4.5.0"},"reference-count":43,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2013,6,7]],"date-time":"2013-06-07T00:00:00Z","timestamp":1370563200000},"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":[[2013,7]]},"abstract":"Abstract<\/jats:title>The association of Epstein\u2013Barr virus (EBV<\/jats:styled-content>) infection with the development of nasopharyngeal carcinoma (NPC<\/jats:styled-content>) is well established. Latent membrane protein 1 (LMP1<\/jats:styled-content>), the major oncogene encoded by EBV<\/jats:styled-content>, is believed to play a crucial role in NPC<\/jats:styled-content> pathogenesis by virtue of its ability to constitutively activate multiple cell signalling pathways. The LKB1\u2013AMPK<\/jats:styled-content> pathway is a master regulator of cellular metabolism that, via modulation of energy metabolism, has tumour suppressor activity. In this study we identify a novel ability of LMP1<\/jats:styled-content> to inhibit the LKB1\u2013AMPK<\/jats:styled-content> pathway through phosphorylation of LKB1<\/jats:styled-content> at serine 428 with subsequent suppression of the phosphorylation of AMPK<\/jats:styled-content> and its substrates, ACC<\/jats:styled-content> and Raptor. We show that MEK<\/jats:styled-content>\/ERK\u2013MAPK<\/jats:styled-content> signalling, activated by the CTAR1<\/jats:styled-content> domain of LMP1<\/jats:styled-content>, is responsible for LKB1\u2013AMPK<\/jats:styled-content> inactivation. In addition, reactivation of AMPK<\/jats:styled-content> signalling by AMPK<\/jats:styled-content> activator, AICAR<\/jats:styled-content>, abolished LMP1<\/jats:styled-content>\u2010induced cellular transformation (proliferation and anchorage\u2010independent growth) in nasopharyngeal epithelial cells. Immunohistochemical staining revealed that a low level of phosphorylated AMPK<\/jats:styled-content> is common in primary NPC<\/jats:styled-content> specimens, and that this correlated significantly with the expression of LMP1<\/jats:styled-content>. AICAR<\/jats:styled-content> treatment inhibited the proliferation and anchorage\u2010independent growth of NPC<\/jats:styled-content> cells as well as potentiating the cytotoxic effect of the chemotherapeutic drug 5\u2010fluorouracil. The current findings demonstrate that LMP1<\/jats:styled-content>\u2010mediated AMPK<\/jats:styled-content> inactivation contributes to the proliferation and transformation of epithelial cells, thereby implicating the LKB1\u2013AMPK<\/jats:styled-content> pathway in the EBV<\/jats:styled-content>\u2010driven pathogenesis of NPC<\/jats:styled-content>. Our findings also suggest that AMPK<\/jats:styled-content> activators could be used to enhance the efficacy of conventional chemotherapeutic agents in the treatment of local and metastatic NPC<\/jats:styled-content>. Copyright \u00a9 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.<\/jats:bold><\/jats:p>","DOI":"10.1002\/path.4201","type":"journal-article","created":{"date-parts":[[2013,4,17]],"date-time":"2013-04-17T09:02:07Z","timestamp":1366189327000},"page":"336-346","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Inhibition of the LKB1\u2013AMPK<\/scp> pathway by the Epstein\u2013Barr virus\u2010encoded LMP1<\/scp> promotes proliferation and transformation of human nasopharyngeal epithelial cells"],"prefix":"10.1002","volume":"230","author":[{"given":"Angela Kwok\u2010Fung","family":"Lo","sequence":"first","affiliation":[{"name":"Cancer Research UK Cancer Centre, School of Cancer Sciences University of Birmingham Vincent Drive Edgbaston, Birmingham B15 2TT UK"},{"name":"Department of Anatomical and Cellular Pathology, Li Ka Shing Institute of Health Science The Chinese University of Hong Kong Prince of Wales Hospital Shatin Hong 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