Prostaglandin Dehydrogenase and Lung Cancer

Available evidences indicate that aberrant expression of the enzymes involved in arachidonic acid metabolism may contribute significantly to the development of lung cancer. Notable examplesare the increased expressionof cyclooxygenase-2 (COX-2)and PQE2 synthase in non-small cell lung cancer (NSCLC)resulting in elevated level of PGE2which may induce local immunosuppression, a condition that favors tumor growth. However, level of PGE2is not only controlled by synthetic enzymes but also by catabolic enzymes, a fact that has been overlooked in studying prostaglandins and cancer. We, therefore, hypothesize that NAD+- linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH),the key enzyme involved in biological inactivation of PGE2,isdown regulated in NSCLCresultingin an impaired catabolism of PGE2.Accordingly, 15-PGDHmay be considered an anti-oncogene. We plan to provide evidences that 15-PGDHmay act as an anti-oncogene both in human lung adenocarcinoma A549ceJJsas weJJasin a murinecancer model. Specific aimsinclude: (1) Is 15-PGDH expression down regulated in human lung cancer? (2) Generation and characterization of 15-PGDH overexpressing A549 cells; (3) Does overexpression of 15-PGDHin A549 cells lead to inhibition of tumorigenesis in athymic mice? The results of the proposed research should provide convincing evidences that 15-PGDHmay act as an anti-oncogene and that 15-PGDHhas the potential to become a novel therapeutic for clinical cancer gene therapy.