The COX-2 enzyme, induced during various modes of cell activation, catalyzes the rate-limiting steps in the conversion of cellular lipids into prostaglandins (PG). Recent data strongly implicate the critical role of COX-2 pathway in cancer development and progression. Complex cellular mechanisms control the precise regulation of expression of the COX-2 gene; for example, regulation at transcriptional and post-transcriptional levels is important. Once induced, the COX-2 enzyme couples to specific downstream pathways, such as the cell surface PG receptor system or the nuclear peroxisomal proliferators activator receptors (PPAR). In the context of tumor biology, the COX-2 enzyme metabolizes multiple substrates, for example, free arachidonate and endocannabinoids. This proposal will examine mechanisms of COX-2 regulation and function in the context of tumor biology.
The first aim of the proposal is based on the hypothesis that the COX-2 enzyme is aberrantly induced in tumors due in part to the function of the RNA binding protein HuR. We have recently shown that the RNA binding protein HuR regulates COX-2 gene expression at the level of mRNA transport and stability. We will further explore the mechanisms of how HuR achieves the stabilization of COX-2 mRNA. We will also examine if HuR expression or activity is critical in exaggerated COX-2 that occurs in cancer. The transgenic mouse model of COX-2 induced mammary tumor formation will be used to obtain in vivo correlates of HuR involvement in COX-2 mRNA expression.
The second aim of the proposal seeks to obtain novel mechanistic insights into COX-2 function. It is generally accepted that the COX-2 enzyme couples to the cell surface PG receptor and the nuclear PPAR receptors. Precisely how this is achieved and how cellular controls are exerted to differentially regulate COX-2 coupling to different effector pathways is poorly understood. We hypothesize that differential substrate utilization (arachidonate versus endocannabinoids) is a mechanism that determines if COX-2 couples to the cell surface versus nuclear receptor pathways. Furthermore, differential expression and subcellular localization of effector systems may determine coupling to the COX-2 pathway. These issues will be investigated in cell culture systems of endothelial cells, mammary epithelial cells and the transgenic model of mammary tumorigenesis. Overall, the proposed lines of investigation will likely procure additional mechanistic insights relevant to the role of COX-2 in tumor biology. Synergy of PPG cores and projects is anticipated to greatly enhance this particular project. In addition, this project will contribute to the PPG by providing unique insights into the role of COX-2 in mammary tumorigenesis. Such efforts may ultimately lead to novel mechanism-based chemopreventive approaches in human cancer.
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