Prostaglandin D and skin cancer prevention

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DESCRIPTION (provided by applicant): Skin cancer is the most common cancer in the United States, with over 1,300,000 new cases per year. The overall goals are to understand how prostaglandin pathways influence development of skin tumors and use the information to improve cancer chemoprevention. The prostaglandin cascade makes prostaglandins E2, D2 (PGE2, PGD2), and other prostanoids. PGD2 promotes tumors in the skin and other organs. For bowel tumors, experiments showed that adenoma-prone ApcMin/+ mice had 50% more tumors when deficient in hematopoietic prostaglandin D synthase (H-PGDS). Conversely, mice had 70% fewer tumors, if they had a transgene causing high levels of H-PGDS. Thus, PGD2 production appears to suppress tumors. Niacin dramatically raises blood levels of PGD2 (causing flushing). The rise in PGD2 is due to the G-protein- coupled nicotinic acid receptor, which stimulates the prostaglandin cascade in Langerhans cells in the skin. Thus, the hypotheses are: (i) PGD2 production may suppress skin tumors, similar to the effect observed for bowel tumors and (ii) niacin may be a chemopreventive agent, due to niacin-responsive Langerhans cells in skin. The proposed experiments will manipulate PGD2 production and assess effects on a mouse model of skin cancer. Specific Aims are: (1) Define effects of H-PGDS transgenes and H-PGDS knockouts on UV-induced skin tumors in heterozygous p53 knockout mice; (2) define effects of dietary niacin on UV-induced skin tumors in heterozygous p53 knockout mice. Significance: Results should give new insight into roles and mechanisms of prostaglandins in tumor growth. Niacin as a booster of PGD2 may emerge as an agent to be studied for chemoprevention of skin cancer.