Induction of cyclooxygenase-2 by Epstein-Barr virus latent membrane protein 1 is involved in vascular endothelial growth factor production in nasopharyngeal carcinoma cells.
Cyclooxygenase-2 (COX-2) is an inducible form of COX and is overexpressed in diverse tumors, raising the possibility of a role for COX-2 in carcinogenesis. In addition, COX-2 contributes to angiogenesis. The Epstein-Barr virus (EBV) oncoprotein, latent membrane protein 1 (LMP1), is detected in at least 70% of nasopharyngeal carcinoma (NPC) and all EBV-infected preinvasive nasopharyngeal lesions. We found that in specimens of LMP1-positive NPC, COX-2 is frequently expressed, whereas LMP1-negative NPC rarely express the enzyme. We next found that expression of LMP1 in EBV-negative nasopharyngeal epithelial cells induced COX-2 expression. Coexpression of IkappaBalpha(S32A/S36A), which is not phosphorylated and prevents NF-kappaB activation, with LMP1 showed that NF-kappaB is essential for induction of COX-2 by LMP1. We also demonstrate that NF-kappaB is involved in LMP1-induced cox-2 promoter activity with the use of reporter assays. Two major regions of LMP1, designated CTAR1 and CTAR2, are signal-transducing domains of LMP1. Constructs expressing either CTAR1 or CTAR2 induce COX-2 but to a lesser extent than wild-type LMP1, consistent with the ability of both regions to activate NF-kappaB. Furthermore, we demonstrate that LMP1-induced COX-2 is functional because LMP1 increased production of prostaglandin E(2) in a COX-2-dependent manner. Finally, we demonstrate that LMP1 increased production of vascular endothelial growth factor (VEGF). Treatment of LMP1-expressing cells with the COX-2-specific inhibitor (NS-398) dramatically decreased production of VEGF, suggesting that LMP1-induced VEGF production is mediated, at least in part, by COX-2. These results suggest that COX-2 induction by LMP1 may play a role in angiogenesis in NPC.
Murono
S
S
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
Inoue
H
H
Tanabe
T
T
Joab
I
I
Yoshizaki
T
T
Furukawa
M
M
Pagano
J S
JS
D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D004790:Enzyme Induction; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008222:Lymphokines / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008565:Membrane Proteins; D016328:NF-kappa B / Q000502:physiology; D009303:Nasopharyngeal Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000821:virology; D009389:Neovascularization, Pathologic / Q000209:etiology*; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014763:Viral Matrix Proteins / Q000502:physiology*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016228:Endothelial Growth Factors; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014763:Viral Matrix Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone