Abstract
Cyclooxygenase-2 (COX-2) has been implicated in a variety of human malignancies and, accordingly, COX-2 selective inhibitors are being investigated as important chemopreventive and therapeutic agents. How COX-2 overexpression results in tumorigenesis and how COX-2 selective agents mediate their chemopreventive effects are issues that remain poorly understood. Here we report that the tumor suppressor p53 upregulates COX-2 expression and that COX-2 can in turn inhibit p53-dependent transcription. Additionally, a COX-2-selective inhibitor potentiates p53-induced apoptosis, which also supports the notion that COX-2 activity appears to interfere with p53 function. Expression of exogenous COX-2 in p53 wild-type cells does not affect the cytoplasmic or nuclear levels of p53, suggesting that COX-2 may not affect p53 turnover or subcellular localization. We further demonstrate that endogenous COX-2 interacts with p53 and that COX-2 and p53 interactions are a physiologically relevant event. Thus, p53 upregulates COX-2 and COX-2 in turn appears to negatively affect p53 activity via mechanisms that could involve physical interactions between COX-2 and p53. Based on our results, we propose that p53-dependent upregulation and activation of COX-2 appear to be yet another novel mechanism by which p53 could abate its own growth-inhibitory and apoptotic effects.
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Acknowledgements
We thank Dr Bert Vogelstein for providing the p53-inducible DLD1 human colon cancer cells as well as pCMV-p53 and PG13-Luc constructs. We thank Dr Richard Kulmacz for providing us with the pSG5-COX-2 expression vector. Also, we thank Dr Thomas Chittenden for providing us with pGL3-PUMA promoter construct. This work was supported in part by the National Institutes of Health Grants CA105300, CA086945 and United States Army PCRP Grant PC030519.
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Corcoran, C., He, Q., Huang, Y. et al. Cyclooxygenase-2 interacts with p53 and interferes with p53-dependent transcription and apoptosis. Oncogene 24, 1634–1640 (2005). https://doi.org/10.1038/sj.onc.1208353
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DOI: https://doi.org/10.1038/sj.onc.1208353
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