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The Tobacco-specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Is a β-Adrenergic Agonist and Stimulates DNA Synthesis in Lung Adenocarcinoma via β-Adrenergic Receptor-mediated Release of Arachidonic Acid
Cancer Research (1999)
  • Hildegard M. Schuller, University of Tennessee, Knoxville
  • Patricia K. Tithof, University of Tennessee - Knoxville
  • Michelle Williams, University of Tennessee - Knoxville
  • Howard K. Plummer III, University of Tennessee - Knoxville
Abstract

Lung cancer is the leading cause of death in the United States, and it demonstrates a strong etiological association with smoking. The nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) reproducibly induces pulmonary adenocarcinomas (ACs) in laboratory rodents and is considered an important contributing factor to the high lung cancer burden observed in smokers. It has been shown that the development of NNK-induced ACs in mice is reduced by inhibitors of cyclooxygenase and lipoxygenase and that the growth of human AC cell lines is regulated by β-adrenergic receptors. On the basis of structural similarities of NNK with classic β-adrenergic agonists, we tested the hypothesis that NNK stimulates the growth of human AC cells via agonist-binding to β-adrenergic receptors, resulting in the release of arachidonic acid (AA). In support of this hypothesis, radioreceptor assays with transfected CHO cell lines stably expressing the human β1- or β2-adrenergic receptor demonstrated high affinity binding of NNK to each of these receptors. Two human AC cell lines expressed β1- and β2-adrenergic receptors by reverse transcription-PCR and responded to NNK with the release of AA and an increase in DNA synthesis. β-Adrenergic antagonists completely blocked the release of AA and increase in DNA synthesis. The cyclooxygenase inhibitor aspirin and the 5-lipoxygenase inhibitor MK-886 both partially inhibited DNA synthesis in response to NNK. Our findings identify the direct interaction of NNK with β-adrenergic, AA-dependent pathways as a novel mechanism of action which may significantly contribute to the high cancer-causing potential of this nitrosamine. Moreover, NNK may also contribute to the development of smoking-related nonneoplastic disease via this mechanism. DOI:

Keywords
  • lung cancer,
  • smoking,
  • β-adrenergic receptors,
  • NNK
Publication Date
September 15, 1999
Citation Information
Hildegard M. Schuller, Patricia K. Tithof, Michelle Williams and Howard K. Plummer III. "The Tobacco-specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Is a β-Adrenergic Agonist and Stimulates DNA Synthesis in Lung Adenocarcinoma via β-Adrenergic Receptor-mediated Release of Arachidonic Acid" Cancer Research Vol. 59 Iss. 18 (1999)
Available at: http://works.bepress.com/hildegard_schuller/31/