Loss of 15-hydroxyprostaglandin dehydrogenase increases prostaglandin E2 in pancreatic tumors.
OBJECTIVE
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.
Pham
Hung
H
Department of Medicine, Hirshberg Laboratories for Pancreatic Cancer Research, and David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1786, USA. htpham@mednet.ucla.edu
Chen
Monica
M
Li
Aihua
A
King
Jonathan
J
Angst
Eliane
E
Dawson
David W
DW
Park
Jenny
J
Reber
Howard A
HA
Hines
O Joe
OJ
Eibl
Guido
G
D002070:Butadienes / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000032:analysis; D015232:Dinoprostone / Q000096:biosynthesis*; D015536:Down-Regulation; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000172:deficiency*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism
D002070:Butadienes; D009570:Nitriles; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C113580:U 0126; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051546:Cyclooxygenase 2; D020929:Mitogen-Activated Protein Kinase Kinases; D015232:Dinoprostone