Regulation of nonsmall‐cell lung cancer stem cell like cells by neurotransmitters and opioid peptides

Nonsmall‐cell lung cancer (NSCLC) is the leading type of lung cancer and has a poor prognosis. We have shown that chronic stress promoted NSCLC xenografts in mice via stress neurotransmitter‐activated cAMP signaling downstream of beta‐adrenergic receptors and incidental beta‐blocker therapy was reported to improve clinical outcomes in NSCLC patients. These findings suggest that psychological stress promotes NSCLC whereas pharmacologically or psychologically induced decreases in cAMP may inhibit NSCLC. Cancer stem cells are thought to drive the development, progression and resistance to therapy of NSCLC. However, their potential regulation by stress neurotransmitters has not been investigated. In the current study, epinephrine increased the number of cancer stem cell like cells (CSCs) from three NSCLC cell lines in spheroid formation assays while enhancing intracellular cAMP and the stem cell markers sonic hedgehog (SHH), aldehyde dehydrogenase‐1 (ALDH‐1) and Gli1, effects reversed by GABA or dynorphin B via Gαi‐mediated inhibition of cAMP formation. The growth of NSCLC xenografts in a mouse model of stress reduction was significantly reduced as compared with mice maintained under standard conditions. Stress reduction reduced serum levels of corticosterone, norepinephrine and epinephrine while the inhibitory neurotransmitter γ‐aminobutyric acid (GABA) and opioid peptides increased. Stress reduction significantly reduced cAMP, VEGF, p‐ERK, p‐AKT, p‐CREB, p‐SRc, SHH, ALDH‐1 and Gli1 in xenograft tissues whereas cleaved caspase‐3 and p53 were induced. We conclude that stress neurotransmitters activate CSCs in NSCLC via multiple cAMP‐mediated pathways and that pharmacologically or psychologically induced decreases in cAMP signaling may improve clinical outcomes in NSCLC patients. What's new? Despite significant reduction in smoking, the incidence of non small‐cell lung cancer (NSCLC) has not significantly decreased. Here the authors uncover a novel link between NSLC and psychological stress. They show that the stress neurotransmitter epinephrine increases the levels of cancer stem cell markers and cancer stem cell like cells in NSCLC cell lines. Importantly, stress reduction inhibited NSCLC growth in vivo by increasing systemic levels of the inhibitory neurotransmitter γ‐aminobutyric acid and opioid peptides that inhibited the cAMP‐driven activation of cancer stem cells underscoring the important influence of stress management on cancer development.