Nitric oxide upregulates the cyclooxygenase-2 expression through the cAMP-response element in its promoter in several cancer cell lines

Abstract

We previously showed that nitric oxide (NO) induces overexpression of cyclooxygenase-2 (COX-2) and production of prostaglandin E 2 in cancer cells. Here, we investigated the mechanisms by which NO induces COX-2 expression in cancer cells. We found that the cAMP-response element (CRE) is a critical factor in NOinduced COX-2 expression in all cells tested. We found that in cancer cells, three transcription factors (TFs) -cAMP response element-binding protein (CREB), activating transcription factor-2 (ATF-2) and c-jun, bound the CRE in the COX-2 promoter, and their activities were increased by addition of the NO donor, S-nitroso-Nacetyl-D,L-penicillamine (SNAP). NO-induced activation of soluble guanylate cyclase (sGC), p38 and c-Jun NH 2 -terminal kinase (JNK) upregulated the three TFs, leading to COX-2 overexpression. Addition of dibutyryl-cGMP (db-cGMP) induced COX-2 expression in a manner similar to SNAP; this induction was blocked by a p38 inhibitor (SB202190), but not by a JNK inhibitor (SP600125). NO-induced cGMP was found to activate CREB and ATF-2 in a p38, but not c-jun-dependent manner, while NO induced JNK in a cGMP-independent manner, leading to subsequent activation of c-jun and ATF-2. These results suggest that the low concentrations of endogenous NO present in cancer cell may induce the expression of many genes, including COX-2, which promotes the growth and survival of tumor cells.

Inhibitory action of eugenol compounds on the production of nitric oxide in RAW264.7 macrophages

“…Expression of COX-2 is stimulated by NO through the cAMP-response element (14), and thus, the cytotoxicity of NO has been considered to be closely related to the action of increased prostaglandins resulting from the induction of COX-2 (10). Several lines of evidence showed that anti-inflammatory action of eugenol compounds depends on the inhibition of the COX-2 expression (6,13,17).…”

“…Cyclooxygenase (COX-2), the rate-limiting enzyme in the sytnthesis of prostanoids, is responsible for the development of inflammation, and its expression is dependent on the NO levels (14). Effect of eugenol compounds on the COX-2 expression was examined in the LPS-stimulated RAW264.7 cells.…”

Different impacts of saturated and unsaturated free fatty acids on COX-2 expression in C2C12myotubes

“…In this regard, a recent study demonstrated that both DNA binding and transcriptional activation of NF-B began to rise in cultured myotubes after an 8-h incubation with palmitate (24). Moreover, p38 has been shown to directly regulate NF-B phosphorylation and its nuclear localization in cardiac myocytes (55), and direct involvement of the p38-ATF-2 pathway in the regulation of COX-2 expression has also been reported in other cell types (23,43). Supporting this notion is our observation that SB-203580 failed to reverse the IB degradation elicited by palmitate treatment (Fig.…”

MSK1 and MSK2 Inhibit Lipopolysaccharide-Induced Prostaglandin Production via an Interleukin-10 Feedback Loop

“…It has been also proposed that in macrophages the CRE site can be occupied by an AP-1 complex, as a cox-2 reporter could be repressed by a dominant negative c-jun construct (12). A role for c-jun in cox-2 induction has also been shown in other cell types (13,14). A recent study reporting a more detailed characterization of the mouse cox-2 promoter has helped resolve these issues.…”