title: Social stress promotes and γ-aminobutyric acid inhibits tumor growth in mouse models of non-small cell lung cancer.
abstract: Psychologic distress is associated with increased lung cancer incidence and mortality. We have shown that non-small cell lung cancer (NSCLC) cells in vitro are stimulated by the cyclic AMP (cAMP)-dependent activation of cAMP-responsive element binding protein (CREB) and extracellular signal-regulated kinase (ERK) downstream of β-adrenergic receptors and that this pathway is inhibited by the neurotransmitter γ-aminobutyric acid (GABA). Because the stress neurotransmitters noradrenalin and adrenalin are β-adrenergic agonists, the current study has tested the hypothesis that social stress stimulates NSCLC growth in vivo and that GABA inhibits this effect. Social stress was induced in mice carrying xenografts from two NSCLC cell lines in the presence and absence of treatment with GABA. Xenograft sizes were measured after 30 days. Noradrenalin, adrenalin, cortisol, GABA, and cAMP were measured in blood and tumor tissues by immunoassays. Expression of nicotinic receptors in the xenografts was assessed by real-time PCR and Western blotting. Protein expression of phospho (p)-CREB, CREB, phospho (p)-ERK, ERK, and glutamate decarboxylase (GAD) 65 and 67 were determined by Western blotting. Xenograft sizes in stress-exposed mice were significantly increased. Nicotinic acetylcholine receptor (nAChR) subunits α3, α4, α5, and α7 in xenograft tissues showed posttranscriptional induction. Noradrenalin, adrenalin, and cortisol were elevated in serum and xenograft tissue whereas GABA was suppressed. Levels of cAMP, p-CREB, and p-ERK were increased whereas GAD65 and GAD67 were suppressed in tumor tissue. Treatment with GABA reversed the effects of stress. Our findings suggest that social stress stimulates NSCLC by increasing nAChR-mediated stress neurotransmitter signaling and that GABA is a promising novel agent for NSCLC intervention.
authors.affiliation: Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA.
authors.forename: Hussein A N
authors.initials: HA
authors.lastname: Al-Wadei
authors.forename: Howard K
authors.initials: HK
authors.lastname: Plummer
authors.forename: Mohammad F
authors.initials: MF
authors.lastname: Ullah
authors.forename: Benjamin
authors.initials: B
authors.lastname: Unger
authors.forename: Joel R
authors.initials: JR
authors.lastname: Brody
authors.forename: Hildegard M
authors.initials: HM
authors.lastname: Schuller
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004837:Epinephrine / Q000097:blood; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D018682:GABA Agents / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008175:Lung Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012944:Social Support; D013315:Stress, Psychological / Q000150:complications*; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D018682:GABA Agents; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D005680:gamma-Aminobutyric Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D006854:Hydrocortisone; D009638:Norepinephrine; D004837:Epinephrine