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.