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[Cancer Research 59, 4356-4362, September 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 4356-4362, September 1, 1999]
© 1999 American Association for Cancer Research

Experimental Therapeutics

Increased Cyclooxygenase-2 Expression in Human Pancreatic Carcinomas and Cell Lines

Growth Inhibition by Nonsteroidal Anti-Inflammatory Drugs1

Miguel A. Molina, Marta Sitja-Arnau2, Michael G. Lemoine2, Marsha L. Frazier and Frank A. Sinicrope3

Departments of Epidemiology [M. A. M., M. S-A., M. L. F.] and Gastrointestinal Medical Oncology and Digestive Diseases [M. G. L., F. A. S.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Cyclooxygenase (COX)-2 mRNA and protein expression were found to be frequently elevated in human pancreatic adenocarcinomas and cell lines derived from such tumors. Immunohistochemistry demonstrated cytoplasmic COX-2 expression in 14 of 21 (67%) pancreatic carcinomas. The level of COX-2 mRNA was found to be elevated in carcinomas, relative to histologically normal pancreas from a healthy individual, as assessed by reverse transcription-PCR. COX-2 protein expression was detected by the Western blot assay in three of five pancreatic carcinoma cell lines (BxPC-3, Capan-1, and MDAPanc-3), whereas COX-1 protein was detected in two of the five cell lines (BxPC-3 and Capan-1). Increased levels of COX-2 mRNA were found in four of five cell lines, and only in PANC-1 cells was the low level of transcript comparable to that in the normal pancreas. The level of COX-2 mRNA was positively correlated with the differentiation status of the tumor of origin for each cell line, COX-2 protein expression was up-regulated by epidermal growth factor when the cells were grown in absence of serum. Finally, two nonsteroidal anti-inflammatory drugs, sulindac sulfide and NS398, produced a dose-dependent inhibition of cell proliferation in all pancreatic cell lines tested. No correlation was found between the level of COX-2 or COX-1 expression and the extent of growth inhibition. Treatment of BxPC-3 cells with sulindac sulfide and NS398 resulted in an induction of COX-2 expression. Our findings indicate that COX-2 up-regulation is a frequent event in pancreatic cancers and suggest that nonsteroidal anti-inflammatory drugs may be useful in the chemoprevention and therapy of pancreatic carcinoma.




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