Skip to main content
Article
Nongenomic β Estrogen Receptors Enhance β1 Adrenergic Signaling Induced by the Nicotine-Derived Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Human Small Airway Epithelial Cells
Cancer Research (2007)
  • Mourad Majidi, University of Tennessee - Knoxville
  • Hussein A. Al-Wadei, University of Tennessee - Knoxville
  • Takashi Takahashi
  • Hildegard M. Schuller, University of Tennessee, Knoxville
Abstract

Women are at higher risk for the development of lung adenocarcinoma than men; however, the mechanisms responsible for this are poorly understood. In lung adenocarcinoma cells, the estrogen receptor β (ERβ) is the predominating form. We found that 17β-estradiol enhanced proliferation of the putative cells of origin of lung adenocarcinoma, small airway epithelial cells (HPLD1), in response to the nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Reverse-phase protein microarrays combined with Western blotting revealed that NNK induced phosphorylation of ERβ, an effect that involved stimulation of the adrenergic receptors β1 (β1AR). In transiently transfected cells, β1AR coprecipitated with ERβ, which increased with NNK treatment. ERβ enhanced NNK-induced cyclic AMP accumulation as well as Gαi-mediated mitogen-activated protein kinase/extracellular signal–regulated kinase (ERK) 1/2 activation. Coexpression of β1AR and ERβ activated NNK-mediated ERK1/2 cooperatively. ERβ gene knockdown, as well as coexpression of the dominant negative Ras and Raf, reduced stimulation of ERK1/2 by NNK. Whereas NNK phosphorylated Akt at Thr308 and Ser473, ERβ had no effect on this activity. Luciferase reporter assays showed that, in response to NNK, ERβ stimulated transcription of serum responsive element (SRE) but had a very small effect on the activity of estrogen responsive element (ERE). Together, the phosphorylation of ERβ, the dependence on Gαi proteins, the activation of ERK1/2, and the preferential targeting of SRE over the classic ERE pathway support a role for nongenomic ERβ in the development of smoking-associated lung cancer. This novel cooperation between β1AR and ERβ signaling may contribute to the prominence of lung adenocarcinoma in women. [Cancer Res 2007;67(14):6863–71]. DOI: 10.1158/0008-5472.CAN-07-0483

Publication Date
July 15, 2007
Citation Information
Mourad Majidi, Hussein A. Al-Wadei, Takashi Takahashi and Hildegard M. Schuller. "Nongenomic β Estrogen Receptors Enhance β1 Adrenergic Signaling Induced by the Nicotine-Derived Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Human Small Airway Epithelial Cells" Cancer Research Vol. 67 Iss. 14 (2007)
Available at: http://works.bepress.com/hildegard_schuller/26/