Regulation of vascular endothelial growth factor signaling by nicotine in a manner dependent on acetylcholine-and/or β-adrenergic-receptors in human lung cancer cells
Document Type
Article
Publication Date
2023
Department/School
Chemistry
Publication Title
Cancers
Abstract
In addition to binding to nicotinic acetylcholine receptors (nAChRs), nicotine is known to regulate the β-adrenergic receptors (β-ARs) promoting oncogenic signaling. Using A549 (p53 wild-type) and H1299 (p53-null) lung cancer cells, we show that nicotine treatment led to: increased adrenaline/noradrenaline levels, an effect blocked by treatment with the α7nAChR inhibitor (α-BTX) but not by the β-blocker (propranolol) or the α4β2nAChR antagonist (DhβE); decreased GABA levels in A549 and H1299 cell media, an effect blocked by treatment with DhβE; increased VEGF levels and PI3K/AKT activities, an effect diminished by cell co-treatment with α-BTX, propranolol, and/or DhβE; and inhibited p53 activity in A549 cells, that was reversed, upon cell co-treatment with α-BTX, propranolol, and/or DhβE or by VEGF immunodepletion. VEGF levels increased upon cell treatment with nicotine, adrenaline/noradrenaline, and decreased with GABA treatment. On the other hand, the p53 activity decreased in A549 cells treated with nicotine, adrenaline/noradrenaline and increased upon cell incubation with GABA. Knockdown of p53 led to increased VEGF levels in the media of A549 cells. The addition of anti-VEGF antibodies to A549 and H1299 cells decreased cell viability and increased apoptosis; blocked the activities of PI3K, AKT, and NFκB in the absence or presence of nicotine; and resulted in increased p53 activation in A549 cells. We conclude that VEGF can be upregulated via α7nAChR and/or β-ARs and downregulated via GABA and/or p53 in response to the nicotine treatment of NSCLC cells.
Link to Published Version
Recommended Citation
Al Khashali, H., Darweesh, B., Ray, R., Haddad, B., Wozniak, C., Ranzenberger, R., Goel, S., Khalil, J., Guthrie, J., Heyl, D., & Evans, H. (2023). Regulation of vascular endothelial growth factor signaling by nicotine in a manner dependent on acetylcholine-and/or β-adrenergic-receptors in human lung cancer cells. Cancers, 15(23). https://doi.org/10.3390/cancers15235500
Comments
J. Guthrie, D. Heyl, and H. G. Evans are faculty in EMU's Department of Chemistry.
*H. Al Khashali, B. Darweesh, R. Ray, B. Haddad, C. Wozniak, R. Ranzenberger, S.Goel, and J. Khalil are EMU students.