COX Regulation and Function in Tumor Biology

COX-2酶在不同的细胞激活模式下诱导，催化细胞脂质转化为前列腺素(PG)的限速步骤。最近的数据有力地暗示了COX-2通路在肿瘤发生发展中的关键作用。复杂的细胞机制控制着COX-2基因表达的精确调控；例如，转录和转录后水平的调控是重要的。一旦被诱导， COX-2酶偶联到特定的下游通路，如细胞表面PG受体系统或核过氧化体增殖物激活物受体(PPAR)。在肿瘤生物学的背景下，COX-2酶代谢多种底物，例如游离的花生四烯酸和内源性大麻素。这项建议将在肿瘤生物学的背景下研究COX-2的调节和功能的机制。该提案的第一个目的是基于这样一个假设，即在肿瘤中COX-2酶被异常诱导，部分原因是RNA结合蛋白HUR的功能。我们最近发现，RNA结合蛋白HUR 在mRNA转运和稳定性水平上调节COX-2基因的表达。我们将进一步探讨HUR稳定COX-2mRNA的机制。我们还将检查HUR的表达或活性是否在癌症中发生的夸大的COX-2中起关键作用。将利用COX-2诱导的转基因小鼠乳腺肿瘤形成模型，在体内获得HUR参与COX-2mRNA表达的相关性。该提案的第二个目的是寻求获得对COX-2功能的新的机械论见解。人们普遍认为，COX-2酶与细胞表面PG受体和核内PPAR受体偶联。确切地说，这是如何实现的，以及细胞控制是如何实施的，以不同的方式调节COX-2与不同的效应器通路的偶联，人们对此知之甚少。我们假设，不同的底物利用(花生四烯酸和内源性大麻素)是决定环氧合酶-2是否耦合到细胞表面还是核受体途径的机制。此外，效应系统的差异表达和亚细胞定位可能决定与COX-2途径的偶联。这些问题将在内皮细胞、乳腺上皮细胞的细胞培养系统和乳腺肿瘤形成的转基因模型中进行研究。总体而言，拟议的研究路线可能会获得与COX-2在肿瘤生物学中的作用相关的更多机制方面的见解。PPG核心和项目的协同作用预计将极大地加强这一特定项目。此外，这个项目将通过提供对COX-2在乳腺中的作用的独特见解来促进PPG 肿瘤发生学。这些努力可能最终导致人类癌症的新的基于机制的化学预防方法。

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.