COX-2 and p53 interactions and cancer prevention
Principal Investigator: M Sheikh
Abstract: 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.
Funding Period: 2003-09-30 - 2006-08-31
more information: NIH RePORT
- Cyclooxygenase-2 interacts with p53 and interferes with p53-dependent transcription and apoptosisChad A Corcoran
Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA
Oncogene 24:1634-40. 2005..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...
- Genotoxic and endoplasmic reticulum stresses differentially regulate TRB3 expressionChad A Corcoran
Department of Pharmacology, State University of New York, Upstate Medical, Syracuse, New York 13210, USA
Cancer Biol Ther 4:1063-7. 2005..Collectively, these findings highlight the importance of stress-specific signaling cascades as well as point out the seemingly divergent roles that TRB3 may play in the cellular stress response...