COX-2 and p53 interactions and cancer prevention

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DESCRIPTION (provided by applicant): Cyclooxygenase 2 (COX-2) is overexpressed in human malignancies and is a promising target to develop novel chemopreventive strategies. Clinical trials are currently in progress to investigate the efficacy of COX-2 selective non-steroidal anti-inflammatory drugs in the prevention of various types of cancers. However, much remains to be elucidated as to how COX-2-selective agents mediate chemopreventive effects. A better understanding of the molecular mechanisms that regulate COX-2 expression will certainly facilitate the development of more effective and less toxic cancer-preventive strategies. In this regard, the tumor suppressor p53 has been found to promote upregulation of COX-2 mRNA and protein levels. COX-2 has been implicated in positive growth regulation and tumorigenesis while tumor suppressor p53 is a negative regulator of growth. Thus, p53-dependent upregulation of COX-2 appears rather incongruous. It has been proposed that p53-dependent COX-2 upregulation could be a mechanism to abate the apoptotic effects of p53. The work proposed in this two-year pilot study will directly evaluate the hypothesis that p53-dependent COX-2 upregulation is a compensatory response that serves to abate the p53-induced apoptosis. In order to accomplish our goals, we have proposed two specific aims. In Specific Aim 1, we will investigate whether COX-2 negatively affects the function of wild type p53. We will establish tetracycline or doxycycline-inducible COX-2 and p53 double-inducible cells to investigate whether COX-2 negatively affects the function of wild type p53. By using the double-inducible cells that would exhibit simultaneous induction of COX-2 and p53, we will ensure that higher levels of COX-2 are available from the beginning. Thus, if COX-2 negatively affects the function of wild type p53 then it will be instantly available to mediate its effect on p53. In Specific Aim 2, we will abrogate COX-2 expression via RNA interference approach to test the effect of COX-2 deficiency on p53 functions including p53-induced apoptosis. Thus, investigating the molecular mechanisms that control the interplay between COX-2 and p53 activities is relevant and the outcome, if successful, would improve our understanding of the malignant development and progression to further the progress in developing novel, more effective and less toxic cancer-preventive strategies.