Cross-talks between cyclooxygenase-2 and tumor suppressor protein p53: Balancing life and death during inflammatory stress and carcinogenesis.
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.
de Moraes
Emanuela
E
International Agency for Research on Cancer, 150 cours Albert Thomas, F-69372, Lyon Cedex 08, France.
Dar
Nazir Ahmad
NA
de Moura Gallo
Claudia Vitoria
CV
Hainaut
Pierre
P
D000818:Animals; D002471:Cell Transformation, Neoplastic; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D051546:Cyclooxygenase 2