title: Cyclooxygenase-2 expression in human pancreatic adenocarcinomas.
abstract: Cyclooxygenase-2 (COX-2) expression is up-regulated in several types of human cancers and has also been directly linked to carcinogenesis. To investigate the role of COX-2 in pancreatic cancer, we evaluated COX-2 protein expression in primary human pancreatic adenocarcinomas (n = 23) and matched normal adjacent tissue (n = 11) by immunoblot analysis. COX-2 expression was found to be significantly elevated in the pancreatic tumor specimens compared with normal pancreatic tissue. To examine whether the elevated levels of COX-2 protein observed in pancreatic tumors correlated with the presence of oncogenic K-ras, we determined the K-ras mutation status in a subset of the tumors and corresponding normal tissues. The presence of oncogenic K-ras did not correlate with the level of COX-2 protein expressed in the pancreatic adenocarcinomas analyzed. These observations were also confirmed in a panel of human pancreatic tumor cell lines. Furthermore, in the pancreatic tumor cell line expressing the highest level of COX-2 (BxPC-3), COX-2 expression was demonstrated to be independent of Erk1/2 activation. The lack of correlation between COX-2 and oncogenic K-ras expression suggests that Ras activation may not be sufficient to induce COX-2 expression in pancreatic tumor cells and that the aberrant activation of signaling pathways other than Ras may be required for up-regulating COX-2 expression. We also report that the COX inhibitors sulindac, indomethacin and NS-398 inhibit cell growth in both COX-2-positive (BxPC-3) and COX-2-negative (PaCa-2) pancreatic tumor cell lines. However, suppression of cell growth by indomethacin and NS-398 was significantly greater in the BxPC-3 cell line compared with the PaCa-2 cell line (P = 0.004 and P < 0.001, respectively). In addition, the three COX inhibitors reduce prostaglandin E(2) levels in the BxPC-3 cell line. Taken together, our data suggest that COX-2 may play an important role in pancreatic tumorigenesis and therefore be a promising chemotherapeutic target for the treatment of pancreatic cancer.
authors.affiliation: Department of Medicine, Department of Biochemistry and Walther Oncology Center, Indiana University School of Medicine, Indianapolis 46202, USA. myipschn@iupui.edu
authors.forename: M T
authors.initials: MT
authors.lastname: Yip-Schneider
authors.forename: D S
authors.initials: DS
authors.lastname: Barnard
authors.forename: S D
authors.initials: SD
authors.lastname: Billings
authors.forename: L
authors.initials: L
authors.lastname: Cheng
authors.forename: D K
authors.initials: DK
authors.lastname: Heilman
authors.forename: A
authors.initials: A
authors.lastname: Lin
authors.forename: S J
authors.initials: SJ
authors.lastname: Marshall
authors.forename: P L
authors.initials: PL
authors.lastname: Crowell
authors.forename: M S
authors.initials: MS
authors.lastname: Marshall
authors.forename: C J
authors.initials: CJ
authors.lastname: Sweeney
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D002461:Cell Line, Transformed; D003062:Codon / Q000235:genetics; D006224:Cricetinae; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis / Q000235:genetics; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins; D008647:Mesocricetus; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009578:Nitrobenzenes / Q000494:pharmacology; D010179:Pancreas / Q000201:enzymology; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D017354:Point Mutation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013467:Sulindac / Q000494:pharmacology
chemical_list: D003062:Codon; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D013467:Sulindac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007213:Indomethacin