This Article Full Text Full Text (PDF) Perspective on this Article Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hughes, D. Articles by Dannenberg, A. J. Search for Related Content PubMed PubMed Citation Articles by Hughes, D. Articles by Dannenberg, A. J.

NAD⁺-Dependent 15-Hydroxyprostaglandin Dehydrogenase Regulates Levels of Bioactive Lipids in Non–Small Cell Lung Cancer

Authors' Affiliations: Departments of ¹ General Surgery, ² Medicine, ³ Pathology and Laboratory Medicine, ⁴ Cardiothoracic Surgery, and ⁵ Public Health, Weill Cornell Medical College, New York, New York; ⁶ Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; ⁷ Department of Medicine, Ireland Cancer Center, Case Western Reserve University, University Hospitals of Cleveland, and Howard Hughes Medical Institute, Cleveland, Ohio; and ⁸ Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky

Requests for reprints: Andrew J. Dannenberg, Department of Medicine, Weill Cornell Cancer Center, 1300 York Avenue, Room F-206, New York, NY 10065. Phone: 212-746-4403; Fax: 212-746-4885; E-mail: ajdannen{at}med.cornell.edu.

Elevated levels of procarcinogenic prostaglandins (PG) are found in a variety of human malignancies including non–small cell lung cancer (NSCLC). Overexpression of cyclooxygenase-2 and microsomal prostaglandin synthase 1 occurs in tumors and contributes to increased PG synthesis. NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for metabolic inactivation of PGs, is down-regulated in various malignancies. The main objective of this study was to elucidate the effect of loss of 15-PGDH on levels of bioactive lipids in NSCLC. We found that levels of cyclooxygenase-2 and microsomal prostaglandin synthase 1 were commonly increased whereas the amount of 15-PGDH was frequently decreased in NSCLC compared with adjacent normal lung. Reduced expression of 15-PGDH occurred in tumor cells and was paralleled by decreased 15-PGDH activity in tumors. Amounts of PGE₁, PGE₂, and PGF₂, known substrates of 15-PGDH, were markedly increased whereas levels of 13,14-dihydro-15-keto-PGE₂, a catabolic product of PGE₂, were markedly reduced in NSCLC compared with normal lung. Complementary in vitro and in vivo experiments were done to determine whether these changes in PG levels were a consequence of down-regulation of 15-PGDH in NSCLC. Similar to NSCLC, amounts of PGE₁, PGE₂, and PGF₂ were markedly increased whereas levels of 13,14-dihydro-15-keto-PGE₂ were decreased in the lungs of 15-PGDH knockout mice compared with wild-type mice or when 15-PGDH was silenced in A549 lung cancer cells. Collectively, these data indicate that 15-PGDH is commonly down-regulated in NSCLC, an effect that contributes to the accumulation of multiple bioactive lipids in NSCLC.

Key Words: 15-hydroxyprostaglandin dehydrogenase • non–small-cell lung cancer • prostaglandin • tumor suppressor • carcinogenesis