Cyclooxygenase-2 expression in human pancreatic adenocarcinomas

Cyclooxygenase-2 (COX-2) expression is up-regulated in several types of hum an cancers and has also been directly linked to carcinogenesis. To investig ate the role of COX-2 in pancreatic cancer, we evaluated COX-2 protein expr ession in primary human pancreatic adenocarcinomas (n = 23) and matched nor mal adjacent tissue (n = 11) by immunoblot analysis. COX-2 expression was f ound to be significantly elevated in the pancreatic tumor specimens compare d 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 th e tumors and corresponding normal tissues. The presence of oncogenic K-ras did not correlate with the level of COX-2 protein expressed in the pancreat ic adenocarcinomas analyzed. These observations were also confirmed in a pa nel of human pancreatic tumor cell lines, Furthermore, in the pancreatic tu mor cell line expressing the highest level of COX-2 (BxPC-3), COX-2 express ion was demonstrated to be independent of Erk1/2 activation. The lack of co rrelation between COX-2 and oncogenic K-ras expression suggests that Ras ac tivation may not be sufficient to induce COX-2 expression in pancreatic tum or 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 i n both COX-2-positive (BxPC-3) and COX-a-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, Tak en together, our data suggest that COX-2 may play an important role in panc reatic tumorigenesis and therefore be a promising chemotherapeutic target f or the treatment of pancreatic cancer.