Carcinogenesis, Vol. 21, No. 2, 139-146,
February 2000
© 2000 Oxford University Press
Cancer Biology |
Cyclooxygenase-2 expression in human pancreatic adenocarcinomas
1 Department of Medicine, Department of Biochemistry and Walther Oncology Center and
2 Department of Biostatistics, Indiana University School of Medicine,
3 Department of Pathology and Laboratory Medicine and
4 Department of Biology, Indiana University–Purdue University, Indianapolis, IN 46202 and
5 Lilly Research Laboratories, Indianapolis, IN 46285, USA
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.
Abbreviations: COX, cyclooxygenase; DMSO, dimethylsulfoxide; Erk1/2 MAP kinase, extracellular signal-regulated kinase 1 and 2 mitogen-activated protein kinase; FCS, fetal calf serum; LPS, lipopolysaccharide; MEK, MAP kinase kinase; NSAIDS, non-steroidal anti-inflammatory drugs; NSCLC, non-small cell lung cancer; PGE2, prostaglandin E2; PMA, phorbol 12-myristate 13-acetate.
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