CYCLOOXYGENASE AND PGE2 RECEPTOR FUNCTION IN SKIN CANCER

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Ultraviolet light exposure is known to be a complete carcinogen inducing & promoting basal cell and squamous cell carcinoma of the skin. Recent work has shown that significant contributions to squamous cell carcinoma initiation and promotion are made by the cyclooxygenase product prostaglandin B2(PGE2). In recent studies from this lab, UV-induced tumor formation was decreased nearly 60% by treatment of SKH hairless mice with the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib. This protection may also occur in humans. P6~ interacts with specific cellular receptors to regulate cell function. With the recent cloning of four different PGE2 receptors, it is now possible to dissect some of the mechanisms by which prostaglandin receptor signaling may act to enhance UV tumorigenesis. Our preliminary work demonstrates that primary human keratinocytes express both growth-stipulatory (EP2) and growth- inhibitory (EP3) receptors for prostaglandin E2 (PGE2) in significant amounts. Our data shows that high concentrations of PGE2 stimulate proliferation by activating low-affinity EP2 receptors coupled to production of cAMP, while inhibition of proliferation is mediated by high- affinity EP3 receptors which are active at 10-fold lower concentrations of PGE2. The signaling pathways linked to this receptor are poorly defined, as are the conditions for generating quantities of PGE2 which drive its activation. Our preliminary data have shown that transfection of the EP3 receptor into HaCaT cells results in decreased proliferation. In contrast, EP2 sense transfected HaCaTs have increased proliferative rates. EP2 antisense transfection into HaCats reverses this picture. We hypothesize that under basal conditions, PGE2 signaling occurs primarily through the high affinity EP3 receptor linked to COX-1 activity, while inflammation induces signaling via the low affinity EP2 receptor linked to COX-2.We also hypothesize that UV-induced upregulation of COX-2 increases tissue PGE2 levels, driving EP2-mediated proliferation in irradiated cells. Selective COX-2 inhibition, resulting in low nM concentrations of PGE2 produced via COX-l, permits selective stimulation of high affinity EP3 receptors mediating enhanced differentiation. The work proposed will better define the relationship between UV-induced PGE2 formation, cyclooxygenase activity, and EP receptor signaling through extensive characterization of basal and UV effects on EP receptor signaling. EP receptor effects on keratinocyte proliferation, apoptosis and differentiation will be studied as markers of cutaneous neoplasia.