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The tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone stimulates proliferation of immortalized human pancreatic duct epithelia through β-adrenergic transactivation of EGF receptors

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Abstract

Purpose: Pancreatic ductal adenocarcinoma is an aggressive smoking-associated human cancer in both men and women. The nicotine-derived 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is thought to contribute to the development of these neoplasms in smokers through genotoxic effects. However, NNK has been recently identified as an agonist for both β1- and β2-adrenergic receptors. Binding of NNK to these receptors stimulates proliferation of pulmonary and pancreatic adenocarcinomas cells in vitro and in hamster models. The goal of this study was to elucidate the NNK effects on the signal transduction pathways downstream of both β1- and β2-adrenergic receptors in immortalized human pancreatic HPDE6-c7 cells. Methods: The HPDE6-c7 cells are developed from normal pancreatic duct epithelial cells which are the putative cells of origin of pancreatic ductal adenocarcinoma. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT) cell proliferation assays, Western blot and cyclic AMP assays were employed to demonstrate the effects of NNK and other β1- and β2-adrenergic agonists and antagonist treatments on these cells. Results: MTT cell proliferation assays demonstrated that NNK and the classic β-adrenergic agonist, isoproterenol, increased cell proliferation in HPDE6-c7 cells. Western blot and cyclic AMP assays demonstrated that NNK treatments also resulted in: (1) transactivation of the epidermal growth factor receptor, EGFR, (2) an increase in intracellular cyclic AMP accumulation, and (3) phosphorylation of mitogen-activated protein kinase, Erk1/2. The proliferative response to NNK and isoproterenol were inhibited by the use of beta-blockers (propranolol), and the inhibitors of adenylyl cyclase (SQ 22536), EGFR-specific tyrosine kinase (AG 1478) and Erk (PD 98059). Conclusion: These findings suggest that the NNK -mediated β-adrenergic receptor transactivation of the EGFR and phosphorylation of Erk1/2 in immortalized human pancreatic duct epithelial cells as a novel mechanism might contribute to the development of tobacco-associated pancreatic carcinogenesis.

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Abbreviations

AA:

Arachidonic acid

AG1478:

4-(3-Chloroanillino)-6,7-dimethoxyquinazoline

EGFR:

Epidermal growth factor receptor

ERK:

Extracellular signal-regulated kinase

GPCR:

G protein-coupled receptors

IBMX:

3-isobutyl 1-methylxanthine

NNK:

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

MAPK:

Mitogen-activated protein kinase

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide

PD98059:

2′-amino-3′methoxyflavone

SQ 22536:

9-(tetrahydro-2-furanyl)−9 H-6-amine

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Acknowledgements

Grant support: This work was supported by Public Health Service Grant RO1 CA042829 with the National Cancer Institute.

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Authors and Affiliations

  1. Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN, 37996, USA

    Minoo D. F. Askari & Hildegard M. Schuller

  2. Division of Cellular and Molecular Biology and Department of Pathology, Ontario Cancer Institute/Princess Margaret Hospital, University of Toronto, Toronto, ON, M5G2M9, Canada

    Ming-Sound Tsao

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  1. Minoo D. F. Askari
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Correspondence to Hildegard M. Schuller.

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Askari, M.D.F., Tsao, MS. & Schuller, H.M. The tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone stimulates proliferation of immortalized human pancreatic duct epithelia through β-adrenergic transactivation of EGF receptors. J Cancer Res Clin Oncol 131, 639–648 (2005). https://doi.org/10.1007/s00432-005-0002-7

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