Differential signaling pathways are activated in the Epstein-Barr virus-associated malignancies nasopharyngeal carcinoma and Hodgkin lymphoma.
EBV is associated with the epithelial cancer, nasopharyngeal carcinoma (NPC), and the lymphoid malignancy, Hodgkin lymphoma (HL). The EBV latent membrane proteins 1 and 2A are expressed in these tumors. These proteins activate the phosphatidylinositol 3'-OH kinase (PI3K)/Akt pathway, which is commonly activated inappropriately in malignancy. In this study, the status of Akt activation and its targets, glycogen synthase kinase-3beta (GSK-3beta) and beta-catenin, was investigated in NPC and HL clinical specimens. In the majority of HL and NPC specimens, Akt was activated, indicating an important role for this kinase in the development and/or progression of these tumors. Akt phosphorylates and inactivates GSK-3beta, a negative regulator of the proto-oncoprotein beta-catenin that is aberrantly activated in many cancers. GSK-3beta was phosphorylated and inactivated with concomitant nuclear beta-catenin accumulation in the majority of NPC specimens. The malignant cells of the majority of HL cases, however, did not have inactivated GSK-3beta and lacked nuclear beta-catenin expression. These data indicate that this signaling arm of PI3K/Akt is universal and important in NPC pathogenesis but is apparently not affected in HL. These findings point to a divergence in pathways activated by EBV in different cellular contexts.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
Jennifer A
JA
Morrison
Margaret L
ML
Gulley
Rajadurai
R
Pathmanathan
Nancy
N
Raab-Traub
D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000378:metabolism* / Q000821:virology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D006689:Hodgkin Disease / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D006801:Humans; D051379:Mice; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014763:Viral Matrix Proteins / Q000235:genetics / Q000502:physiology; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014763:Viral Matrix Proteins; D051176:beta Catenin; C494918:AKT1 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3