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pubmed:abstractText |
Abundant evidence supports the role of cyclooxygenase-2 (COX-2) in colorectal cancer. Nitric oxide (NO), a pro-inflammatory signaling factor, may regulate COX-2 expression and activity thereby linking hyper-inflammatory states to cancer susceptibility. Previously we showed that NO induced COX-2 expression. Although NO also activated the beta-catenin.T-cell factor/lymphocyte enhancing factor transcriptional pathway, a direct causal link between this pathway and COX-2 expression was not demonstrated. In this current study, we focused on NO-induced transcriptional activity and elucidated its role in COX-2 expression. NO donors stimulated the expression of peroxisome proliferator-activated receptor-delta and c-myc, both downstream genes of beta-catenin. They also induced the expression of polyoma enhancer activator 3 (PEA3) and increased its DNA-binding activity. To establish a role for PEA3 to beta-catenin-induced COX-2, we transfected RKO cells with beta-catenin and found that beta-catenin increased PEA3 expression. Also, there was higher PEA3 in immortal mouse colon epithelium cells (Apc(Min/)(+)) compared with young adult mouse colon cells (Apc(+/+)). Luciferase reporter assays revealed that, although several transcription factors/coactivator, acting alone or in synergistic combination, induced COX-2 promoter activity, PEA3 was one of the most potent. Interestingly, NO from NO donors or generated endogenously from transfected inducible nitric-oxide synthase, increased PEA3/p300-induced COX-2 promoter activity. We also found that an ETS site (-75/-72) and the NF-IL6 site were responsible for COX-2 activity induced by PEA3, PEA3/p300, and NO. Taken together, our results demonstrated that NO through beta-catenin signaling stimulated PEA3 to increase COX-2 activity. In addition, NO augmented the synergistic interaction between PEA3 and CBP/p300.
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pubmed:affiliation |
Metabolism & Cancer Susceptibility Section, Laboratory of Comparative Carcinogenesis, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702, USA.
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