NAD+-dependent 15-hydroxyprostaglandin dehydrogenase regulates levels of bioactive lipids in non-small cell lung cancer

Duncan Hughes, Taisuke Otani, Peiying Yang, Robert A. Newman, Rhonda K. Yantiss, Nasser K. Altorki, Jeff L. Port, Min Yan, Sanford D. Markowitz, Madhu Mazumdar, Hsin Hsiung Tai, Kotha Subbaramaiah, Andrew J. Dannenberg

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Elevatedlevels of procarcinogenic prostaglandins (PG) are foundin a variety of human malignancies including non-small cell lung cancer (NSCLC). Overexpression of cyclooxygenase- 2 andmicrosomal prostaglandin synthase 1 occurs in tumors andcontributes to increasedP G 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 andmicrosom al prostaglandin synthase 1 were commonly increased whereas the amount of 15-PGDH was frequently decreased in NSCLC compared with adjacent normal lung. Reducedexpression of 15-PGDH occurredin tumor cells andwas paralleled by decreased 15-PGDH activity in tumors. Amounts of PGE1, PGE2, and PGF , 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 were markedly increased whereas levels of 13,14-dihydro-15-keto-PGE2 were decreased in the lungs of 15-PGDH knockout mice comparedwith wild-type mice or when 15-PGDH was silenced in A549 lung cancer cells. Collectively, these data indicate that 15-PGDH is commonly downregulatedin NSCLC, an effect that contributes to the accumulation of multiple bioactive lipids in NSCLC.

Original languageEnglish (US)
Pages (from-to)241-249
Number of pages9
JournalCancer Prevention Research
Volume1
Issue number4
DOIs
StatePublished - Sep 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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