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

Int J Cancer. 2015 Dec 15;137(12):2815-24. doi: 10.1002/ijc.29646. Epub 2015 Jul 2.


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.

Keywords: cAMP signaling; cancer stem cell like cells; cancer stem cell markers; neurotransmitters; non small-cell lung cancer; opioid peptides.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Carcinoma, Non-Small-Cell Lung / psychology
  • Cell Line, Tumor
  • Cell Proliferation
  • Corticosterone / blood
  • Epinephrine / blood
  • Epinephrine / pharmacology
  • Humans
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / psychology
  • Male
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / physiology*
  • Neurotransmitter Agents / blood*
  • Norepinephrine / blood
  • Opioid Peptides / blood*
  • Stress, Psychological / blood
  • Transcription Factors / metabolism
  • Zinc Finger Protein GLI1
  • gamma-Aminobutyric Acid / blood


  • GLI1 protein, human
  • Neurotransmitter Agents
  • Opioid Peptides
  • Transcription Factors
  • Zinc Finger Protein GLI1
  • gamma-Aminobutyric Acid
  • Corticosterone
  • Norepinephrine
  • Epinephrine