Journal Article

β-Adrenergic growth regulation of human cancer cell lines derived from pancreatic ductal carcinomas

D.L. Weddle, P. Tithoff, M. Williams and H.M. Schuller

in Carcinogenesis

Volume 22, issue 3, pages 473-479
Published in print March 2001 | ISSN: 0143-3334
Published online March 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.3.473
β-Adrenergic growth regulation of human cancer cell lines derived from pancreatic ductal carcinomas

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Exocrine ductal carcinoma of the pancreas has been associated with smoking, and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) causes this cancer type in laboratory rodents. Current knowledge on the growth regulation of this malignancy is extremely limited. Recent studies have shown overexpression of cyclooxygenase 2 (COX 2) and 5-lipoxygenase (5-lipox) in exocrine pancreatic carcinomas, suggesting a potential role of the arachidonic acid (AA) cascade in the regulation of this cancer type. In support of this interpretation, our data show high basal levels of AA release in two human cell lines derived from exocrine ductal pancreatic carcinomas. Both cell lines expressed m-RNA for β2-adrenergic receptors and β1-adrenergic receptors. Radio-receptor assays showed that β2-adrenergic receptors predominated over β1-adrenergic receptors. β2-Adrenergic antagonist ICI118,551 significantly reduced basal AA release and DNA synthesis when the cells were maintained in complete medium. DNA synthesis of the cell line (Panc-1) with an activating point mutation in codon 12 of the ki-ras gene was significantly stimulated by NNK when cells were maintained in complete medium and this response was inhibited by the β-blocker ICI118,551, the COX-inhibitor aspirin, or the 5-lipox-inhibitor MK-886. The cell line without ras mutations (BXPC-3) did not show a significant response to NNK in complete medium. When the assays were conducted in serum-free medium, both cell lines demonstrated increased DNA synthesis in response to NNK, an effect inhibited by the β2-blocker, aspirin, or MK-886. Panc-1 cells were more sensitive to the stimulating effects of NNK and less responsive to the inhibitors than BXPC-3 cells. Our findings are in accord with a recent report which has identified NNK as a β-adrenergic agonist and suggest β-adrenergic, AA-dependent regulatory pathways in pancreatic cancer as a novel target for cancer intervention strategies.

Keywords: AA, arachidonic acid; COX 2, cyclooxygenase 2; EGF, epidermal growth factor receptor; FBS, fetal bovine serum; 5-lipox, 5-lipoxygenase; NNK, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

Journal Article.  4640 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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