Conclusion

2012

PLoS ONE

Lung cancer is the leading cause of cancer death; 80–85% of lung cancer cases are non-small cell lung cancer (NSCLC). Smoking is a documented risk factor for the development of this cancer. Although nicotine does not have the ability to initiate carcinogenic events, recent studies have implicated nicotine in growth stimulation of NSCLC. Using three NSCLC cell lines (NCI-H322, NCI-H441 and NCI-H1299), we identified the cooperation of nicotinic acetylcholine receptors (nAChRs) and β-adrenergic receptors (β-ARs) as principal regulators of these effects. Proliferation was measured by thymidine incorporation and MTT assays, and Western blots were used to monitor the upregulation of the nAChRs and activation of signaling molecules. Noradrenaline and GABA were measured by immunoassays. Nicotine-treated NSCLC cells showed significant induction of the α7nAChR and α4nAChR, along with significant inductions of p-CREB and p-ERK1/2 accompanied by increases in the stress neurotransmitter noradrenaline, which in turn led to the observed increase in DNA synthesis and cell proliferation. Effects on cell proliferation and signaling proteins were reversed by the α7nAChR antagonist α-BTX or the β-blocker propranolol. Nicotine treatment also down-regulated expression of the GABA synthesizing enzyme GAD 65 and the level of endogenous GABA, while treatment of NSCLC cells with GABA inhibited cell proliferation. Interestingly, GABA acts by reducing β-adrenergic activated cAMP signaling. Our findings suggest that nicotine-induced activation of this autocrine noradrenaline-initiated signaling cascade and concomitant deficiency in inhibitory GABA, similar to modulation of these neurotransmitters in the nicotine-addicted brain, may contribute to the development of NSCLC in smokers. Our data suggest that exposure to nicotine either by tobacco smoke or nicotine supplements facilitates growth and progression of NSCLC and that pharmacological intervention by β blocker may lower the risk for NSCLC development among smokers and could be used to enhance the clinical outcome of standard cancer therapy.

Section: Introductionmentioning

confidence: 99%

Cooperative Regulation of Non-Small Cell Lung Carcinoma by Nicotinic and Beta-Adrenergic Receptors: A Novel Target for Intervention

Al-Wadei

2012

PLoS ONE

“…The long-term use of these agents may thus significantly contribute to the increased lung cancer risk observed in individuals with chronic obstructive pulmonary disease (COPD) [96]. Efforts to target individual signaling proteins in combination with chemo- or radiation therapy have not significantly improved the prognosis of NSCLC [1]. Additional approaches aimed at normalizing sympathicus hyperactivity are needed to improve clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…Lung cancer is globally the leading cause of cancer deaths, with non-small cell lung carcinoma (NSCLC) predominating [1]. Since the first Surgeon General’s report on the association of smoking with lung cancer in 1964, tobacco control measures have significantly reduced the number of smokers in the US, saving an estimated 8 million lives until today [2].…”

Section: Introductionmentioning

confidence: 99%

Impact of Neuro-Psychological Factors on Smoking-Associated Lung Cancer

2014

Cancers

Smoking has been extensively documented as a risk factor for all histological types of lung cancer and tobacco-specific nitrosamines and polycyclic aromatic hydrocarbons reproducibly cause lung cancer in laboratory rodents. However, the most common lung cancer, non-small cell lung cancer (NSCLC), frequently develops in never smokers and is particularly common in women and African Americans, suggesting that factors unrelated to smoking significantly impact this cancer. Recent experimental investigations in vitro and in animal models have shown that chronic psychological stress and the associated hyperactive signaling of stress neurotransmitters via β-adrenergic receptors significantly promote the growth and metastatic potential of NSCLC. These responses were caused by modulation in the expression and sensitization state of nicotinic acetylcholine receptors (nAChRs) that regulate the production of stress neurotransmitters and the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Similar changes in nAChR-mediated neurotransmitter production were identified as the cause of NSCLC stimulation in vitro and in xenograft models by chronic nicotine. Collectively, these data suggest that hyperactivity of the sympathetic branch of the autonomic nervous system caused by chronic psychological stress or chronic exposure to nicotinic agonists in cigarette smoke significantly contribute to the development and progression of NSCLC. A recent clinical study that reported improved survival outcomes with the incidental use of β-blockers among patients with NSCLC supports this interpretation.

“…Due to differences in clinical behavior, lung cancer is commonly classified into non-small cell lung carcinoma (NSCLC), a family of several histological lung cancer types (adenocarcinoma, squamous cell carcinoma, large cell carcinoma) and small cell lung carcinoma (SCLC), with NSCLC being generally non-responsive to chemotherapy [1]. Smoking has been extensively documented as a leading risk factor for NSCLC and SCLC.…”

Section: Introductionmentioning

confidence: 99%

Effects of tobacco constituents and psychological stress on the beta-adrenergic regulation of non-small cell lung cancer and pancreatic cancer: Implications for intervention

2013

CBM

This review summarizes current preclinical and clinical evidence in support of the hypothesis that smoking and psychological stress have significant cancer promoting effects on non small cell lung cancer and pancreatic cancer via direct and indirect effects on nicotinic receptor-regulated beta-adrenergic signaling. Evidence is provided that targeted pharmacological interference with the resulting hyperactive cAMP-dependent signaling by beta-blockers or by γ-aminobutyric acid as well as positive psychological influences may be highly effective in preventing and improving clinical outcomes of these cancers, provided that appropriate diagnostic protocols are followed to monitor systemic levels of stress neurotransmitters and cAMP.