Cyclooxygenase-2 expression in human pancreatic adenocarcinomas

Michele T. Yip-Schneider, Darlene S. Barnard, Steven D. Billings, Liang Cheng, Douglas K. Heilman, Amy Lin, Steven J. Marshall, Pamela L. Crowell, Mark S. Marshall, Christopher J. Sweeney

Research output: Contribution to journalArticle

250 Scopus citations

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 E2 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.

Original languageEnglish (US)
Pages (from-to)139-146
Number of pages8
JournalCarcinogenesis
Volume21
Issue number2
StatePublished - Feb 28 2000

ASJC Scopus subject areas

  • Cancer Research

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    Yip-Schneider, M. T., Barnard, D. S., Billings, S. D., Cheng, L., Heilman, D. K., Lin, A., Marshall, S. J., Crowell, P. L., Marshall, M. S., & Sweeney, C. J. (2000). Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis, 21(2), 139-146.