Loss of 15-hydroxyprostaglandin dehydrogenase increases prostaglandin E2 in pancreatic tumors

Pancreas. 2010 Apr;39(3):332-9. doi: 10.1097/MPA.0b013e3181baecbe.

Abstract

Objectives: Prostaglandin E2 (PGE2) is a product of cyclooxygenase (COX) and PGE synthase (PGES) and deactivated by 15-hydroxyprostaglandin dehydrogenase (PGDH). Down-regulation of PGDH contributes to PGE2 accumulation in lung and colon cancers but has not been identified in pancreatic cancer.

Methods: Normal human pancreatic and tumor-matched tissues, as well as MiaPaCa-2 and BxPC-3 cell lines, were assessed for COX-2, microsomal PGES-1, PGDH, and snail homolog 1 (SNAI1) and SNAI2 expressions by real-time polymerase chain reaction and Western blotting and PGE2 by enzyme-linked immunosorbent assay.

Results: Normal tissues exhibited low COX-2 messenger RNA (mRNA) and protein expressions and high PGDH mRNA and protein expressions and PGE2 levels at 13 pg/mg of protein. In contrast, tumor tissues exhibited high COX-2 mRNA and protein expressions and low PGDH mRNA and protein expressions and PGE2 levels at 32 pg/mg of protein. Tumor tissues exhibited significantly elevated expressions of SNAI2 mRNA and protein but not SNAI1 because SNAI1 and SNAI2 reportedly down-regulate PGDH expression. The COX-2-positive BxPC-3 but not the COX-2-negative MiaPaCa-2 treated with 100-nmol/L PGE2 induced phosphorylated extracellular signal-related kinase that was blocked by the mitogen-activated protein kinase kinase inhibitor U0126, demonstrating the ability of PGE2 to activate ERK.

Conclusions: These results suggest that enhanced PGE2 production proceeds through the expressions of COX-2 and microsomal PGES-1 and down-regulation of PGDH by SNAI2 in pancreatic tumors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Butadienes / pharmacology
  • Carcinoma, Pancreatic Ductal / enzymology*
  • Cell Line, Tumor
  • Cyclooxygenase 2 / analysis
  • Dinoprostone / biosynthesis*
  • Down-Regulation
  • Humans
  • Hydroxyprostaglandin Dehydrogenases / deficiency*
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Nitriles / pharmacology
  • Pancreatic Neoplasms / enzymology*
  • Snail Family Transcription Factors
  • Transcription Factors / metabolism

Substances

  • Butadienes
  • Nitriles
  • SNAI1 protein, human
  • SNAI2 protein, human
  • Snail Family Transcription Factors
  • Transcription Factors
  • U 0126
  • Hydroxyprostaglandin Dehydrogenases
  • 15-hydroxyprostaglandin dehydrogenase
  • Cyclooxygenase 2
  • Mitogen-Activated Protein Kinase Kinases
  • Dinoprostone