Cross‐talks between cyclooxygenase‐2 and tumor suppressor protein p53: Balancing life and death during inflammatory stress and carcinogenesis

Abstract

Overexpression of Cyclooxygenase-2 (COX-2) is observed in most tumor types. Increased COX-2 activity and synthesis of prostaglandins stimulates proliferation, angiogenesis, invasiveness and inhibits apoptosis. Many stress and proinflammatory signals induce COX-2 expression, including oxyradicals or DNA-damaging agents. The latter also induces p53, a transcription factor often inactivated by mutation in cancer. Several studies have identified complex cross-talks between p53 and COX-2, whereby p53 can either up-or down-regulate COX-2, which in turn controls p53 transcriptional activity. However, the molecular basis of these effects are open to debate, in particular since no p53 binding sequences have been identified in COX-2 regulatory regions. In this review, we summarize the molecular mechanisms by which COX-2 contributes to carcinogenesis and discuss the experimental set-up, results and conclusions of studies analyzing cross-talks between p53 and COX-2. We propose 2 scenarios accounting for overexpression of COX-2 in precursor and cancer lesions. In the ''inflammatory'' scenario, p53, activated by DNA damage induced by oxygen and nitrogen species, recruits NF-kappaB to activate COX-2, resulting in antiapoptotic effects that contribute to cell expansion in inflammatory precursor lesions. In the ''constitutive proliferation'' scenario, oncogenic stress due to activation of growth signaling cascades may upregulate COX-2 promoter independently of NF-kappaB and p53, synergizing with TP53 mutation to promote cancer progression. These 2 scenarios, although not mutually exclusive, may account for the diversity of the correlations between COX-2 expression and TP53 mutation, which vary according to cancer types and biological contexts, and have implications for the use of COX-2 inhibitors in cancer prevention and therapy. ' 2007 Wiley-Liss, Inc.

Gallotannin regulates apoptosis and COX-2 expression via Akt and p38kinase pathway in human lung cancer cell line, A549

“…Many findings have contributed to establishing the relationship between the expression of apoptosis and COX-2 (Benoit et al 2006;de Moraes et al 2007).…”

“…Several signaling pathways are involved in the expression of p53, a tumor-suppressor gene (Hsu et al 2007). Several studies have found that stimulation of COX-2 also induces p53, which accelerates after post-translation modification in response to DNA damage (de Moraes et al 2007) and an increase of p53 results in antiproliferative effects, including cell cycle arrest, DNA repair, or apoptosis (Sengupta and Harris 2005).…”

15-Deoxy-Δ12,14-prostaglandin J2 stabilizes, but functionally inactivates p53 by binding to the cysteine 277 residue

“…Consistent with this report, our data reveal that 15d-PGJ 2 treatment results in the p53 protein accumulation in human breast cancer (MCF-7) cells. Several studies have identified complex crosstalks between p53 and COX-2, whereby p53 can either up-or downregulate COX-2, which in turn controls p53 transcriptional activity (de Moraes et al, 2007). However, the molecular basis of such p53-COX-2 axis is open to debate.…”

The dark side of a tumor suppressor: anti-apoptotic p53

“…Several mechanisms were postulated to contribute to the anti-apoptotic effect of Cox-2 including the metabolism of its pro-apoptotic substrate arachidonic acid and subsequent synthesis of the survival factor prostaglandin, as well as augmenting expression and activity of Bcl-2 and Akt (Figure 4). 148 In addition, Cox-2 appears to directly modulate p53 activity at several levels as firstly, overexpression of Cox-2 was found to promote the binding of p53 to MDM2 resulting in a diminished nuclear accumulation of p53 protein. Consistent with this, Cox-2 inhibitors enhanced chemosensitivity by downregulating HDM2 thereby augmenting p53 stability.…”

“…44,147 Cox-2, a crucial enzyme in prostaglandin synthesis is often overexpressed in many solid tumors and associated with tumor aggressiveness due to its well documented anti-apoptotic and tumor-promoting capabilities. 148,149 Cox-2 was also demonstrated to regulate p53-induced apoptosis, as the rate of cell death following DNA damage was potentiated not only in Cox-2-deficient cells, but also in cells in which Cox-2 activity was suppressed by non-steroidal anti-inflammatory drugs such as NS-398 and celecoxib. Several mechanisms were postulated to contribute to the anti-apoptotic effect of Cox-2 including the metabolism of its pro-apoptotic substrate arachidonic acid and subsequent synthesis of the survival factor prostaglandin, as well as augmenting expression and activity of Bcl-2 and Akt (Figure 4).…”