title: Nicotine enhances proliferation, migration, and radioresistance of human malignant glioma cells through EGFR activation.
abstract: It has been suggested that continued tobacco use during radiation therapy contributes to maintenance of neoplastic growth despite treatment with radiation. Nicotine is a cigarette component that is an established risk factor for many diseases, neoplastic and otherwise. The hypothesis of this work is that nicotine promotes the proliferation, migration, and radioresistance of human malignant glioma cells. The effect of nicotine on cellular proliferation, migration, signaling, and radiation sensitivity were evaluated for malignant glioma U87 and GBM12 cells by use of the AlamarBlue, scratch healing, and clonogenic survival assays. Signal transduction was assessed by immunoblotting for activated EGFR, ERK, and AKT. At concentrations comparable with those found in chronic smokers, nicotine induced malignant glioma cell migration, growth, colony formation, and radioresistance. Nicotine increased phosphorylation of EGFR(tyr992), AKT(ser473), and ERK. These molecular effects were reduced by pharmacological inhibitors of EGFR, PI3K, and MEK. It was therefore concluded that nicotine stimulates the malignant behavior of glioma cells in vitro by activation of the EGFR and downstream AKT and ERK pathways.
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University of Virginia Health System, Jordan Building, Rm. 2221, Charlottesville, VA 22908, USA. ashraf.khalil@virginia.edu
authors.forename: Ashraf A
authors.initials: AA
authors.lastname: Khalil
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Jameson
authors.forename: William C
authors.initials: WC
authors.lastname: Broaddus
authors.forename: Peck Sun
authors.initials: PS
authors.lastname: Lin
authors.forename: Theodore D
authors.initials: TD
authors.lastname: Chung
mesh_terms: D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000502:physiology; D005910:Glioma / Q000473:pathology*; D006801:Humans; D009538:Nicotine / Q000009:adverse effects* / Q000494:pharmacology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000502:physiology; D011836:Radiation Tolerance / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical; D014407:Tumor Cells, Cultured
chemical_list: D009538:Nicotine; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases