title: NAD+-dependent 15-hydroxyprostaglandin dehydrogenase regulates levels of bioactive lipids in non-small cell lung cancer.
abstract: 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 PGF(2alpha), 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 PGF(2alpha) 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.
authors.affiliation: Department of General Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Duncan
authors.initials: D
authors.lastname: Hughes
authors.forename: Taisuke
authors.initials: T
authors.lastname: Otani
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Newman
authors.forename: Rhonda K
authors.initials: RK
authors.lastname: Yantiss
authors.forename: Nasser K
authors.initials: NK
authors.lastname: Altorki
authors.forename: Jeff L
authors.initials: JL
authors.lastname: Port
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
authors.forename: Madhu
authors.initials: M
authors.lastname: Mazumdar
authors.forename: Hsin-Hsiung
authors.initials: HH
authors.lastname: Tai
authors.forename: Kotha
authors.initials: K
authors.lastname: Subbaramaiah
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071876:Prostaglandin-E Synthases; D011453:Prostaglandins / Q000378:metabolism
chemical_list: D011453:Prostaglandins; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases