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

• Published in: International journal of cancer Vol. 121; no. 5; pp. 929 - 937
• Main Authors: de Moraes, Emanuela, Dar, Nazir Ahmad, de Moura Gallo, Claudia Vitoria, Hainaut, Pierre
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.09.2007; Wiley-Liss
• Subjects: Animals; apoptosis; Biological and medical sciences; cancer; Cell Transformation, Neoplastic; COX‐2; COX‐2 inhibitors; Cyclooxygenase 2 - metabolism; DNA damage; Humans; inflammation; Inflammation - metabolism; Medical sciences; p53; Tumor Suppressor Protein p53 - metabolism; Tumors; COX-2 inhibitors; COX-2; Enzyme; Cyclooxygenase 2; Mortality; p53 Protein; DNA damage; Inflammation; Cyclooxygenase 2 inhibitor; Malignant tumor; Carcinogenesis; Stress; p53; Cancerology; TP53 Gene; Cell death; Oxidoreductases; Lesion; Apoptosis; Tumor suppressor gene; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.22899

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.