EP1 prostanoid receptor in ultraviolet carcinogenesis

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DESCRIPTION (provided by applicant): Ultraviolet light B (UVB) is responsible for the majority of cutaneous damage following both acute and long term exposure and is believed to be the single most important etiologic agent in non-melanoma skin cancers (NMSC) development. These skin tumors are by far the most common form of cancer in humans, with over 1 million new cases identified in the United States each year. UVB carcinogenesis has recently been associated with an inflammatory response that includes increases in the cyclooxygenase-2 (COX-2) gene and the subsequent elevation of prostaglandin E2 (PGE2). The importance of COX-2 induction and subsequent PGE2 production in skin tumor formation has been demonstrated in both COX-2 knockout mice as well as in studies using the specific COX-2 inhibitor, celecoxib. The biological actions of PGE2 have been attributed to its signaling through four main receptors EP[1-4]. The recent development of specific EP receptor antagonists now makes it possible to evaluate the contribution of PGE2 to the carcinogenic process by blocking its binding to specific EP receptor(s). While studies in both breast and colon cancer suggest that specific EP receptors stimulate tumor development, the particular EP receptors important in UVB induced skin carcinogenesis have not been identified. The underlying Hypothesis for the proposed studies is that PGE2 signaling through the EP1 receptor contributes to both the acute changes that occur following UVB exposure, as well as to tumor development in response to chronic UVB exposure. Studies in the first specific aim will examine the effects of blocking EP1 receptor activity via administration of the specific EP1 receptor antagonist ONO-8713 alone or in combination with celecoxib, a specific COX-2 inhibitor, on the acute UVB-mediated cutaneous inflammatory response. Studies in specific aim 2 will examine the effects of blocking EP1 receptor activity via administration of the specific EP1 receptor antagonist ONO-8713 alone or in combination with celecoxib, a specific COX-2 inhibitor, on tumor promotion, progression and regression. Finally studies in specific aim 3 will demonstrate directly the importance of EP1 signaling in UVB-induced skin carcinogenesis by testing the susceptibility of EP1 KO mice backcrossed to Skh/hr hairless mice to UVBinduced skin carcinogenesis. These studies offer a unique opportunity to gain insight into the role of the EP1 receptor in the skin carcinogenesis process and potentially provide an important pharmacological approach to preventing or reversing the damaging effects of sunlight exposure.