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Schuller Neurotransmitter receptors and cancer

NOVEL FINDINGS transcription. However, the molecular mechanisms
[61]
of this effect have yet to be defined. Based on the
Three publications [59-61] from the Research Institute inhibitory effects of mecamylamine and VOC blockers
of Pharmacological Sciences, College of Pharmacy, on EGF-1R phosphorylation, nAChRs were the
Seoul National University (Seoul, Republic of Korea) upstream regulators of this β-adrenergic cascade by
have recently revealed additional mechanisms of stimulating the release of Nor and Epi. In accord with
nAChR and β-AR-mediated lung cancer promotion that established mechanisms of stress responses (nAChR-
can potentially be exploited for the targeted prevention mediated opening of VOCs causing release of stress
and therapy of lung cancer and numerous other neurotransmitters by exocytosis from the sympathetic
cancers. These studies showed that NSCLC tissues nervous system and adrenal glands), experimental
from smokers expressed significantly higher levels of chronic stress had significant tumor promoting effects
the phosphorylated insulin-like growth factor-1 receptor on urethane-induced mouse NSCLC and on the
(IGF-1R) than NSCLCs from nonsmokers and that the development of this cancer type in transgenic Kras G12D/+
nicotine-derived carcinogen NNK promoted NSCLC mice via IGF-2-mediated activation of the IGF-1R
tumorigenesis in vitro and in a mouse model by inducing signaling cascade. [60,61] In both animal models these
exocytosis of insulin-like growth factor 2 (IGF-2) that effects were inhibited by the general beta-blocker
phosphorylated the IGF-1 receptor, effects inhibited propranolol or the dihydropyridine VOC blockers
by the neuronal nAChR antagonist mecamylamine, amlodipine or nifedipine. Propranolol also significantly
dyhydropyridine blockers of L-type VOCs as well as prevented the development of NNK-induced lung
by antagonists for β1-and β2-ARs. The investigators tumors in A/J mice, an effect accompanied by
[59]
[61]
reported that the observed IGF-1R phosphorylation suppression of phosphorylated IGF-1R. The authors
was caused by β-AR-mediated stimulation of IGF2 conclude that beta-blockers and VOC blockers should
be further explored for the prevention of lung cancer,
a concept that could rapidly move into clinical trials
because these drugs are already widely used for the
long-term management of cardiovascular disease.

CONCLUSIONS AND FUTURE DIRECTIONS

The reported activation of the IGF-1R signaling cascade
in NSCLC and their normal epithelial precursor cells by
the joint actions of nAChRs, VOCs and β-ARs adds a
novel aspect to the mechanisms of cancer regulation
by neurotransmitter receptors. While cancer research
on the regulatory function of these receptors has
mostly interpreted their modulation of intracellular
signaling pathways as direct events downstream of the
receptors, [20,24,30,45,62,63] the cited three publications [59-61]
instead take into consideration the physiological role
of nAChRs and β-ARs in the release of cell type-
specific products by exocytosis [Figure 1] in response
to increased intracellular Ca . In addition to IGF-2,
2+
β-AR-I agonists also induced the release of AA, EGF,
VEGF, interleukin-6 as well as several cancer stem cell
markers. [36,64-66] In turn, these effects can be caused by
elevated systemic levels of stress neurotransmitters
in response to stress or tobacco exposure, by direct
binding of NNK in tobacco products to β-ARs, or by
medications that are beta-adrenergic agonists. In
Figure 1: Working model illustrating the mechanistic interactions addition, epithelial cancer cells and their respective
of nicotinic acetylcholine receptors, Ca -channels, beta-adrenergic
2+
receptors and the IGF pathway in cancers associated with smoking cancer stem cells synthesize and release their own
and psychological stress. NNK: nicotine-derived nitrosamine Epi and Nor upon activation of nAChRs by nicotine or
ketone; nAChRs: nicotinic acetylcholine receptors; IGF-1R: insulin- nicotine-derived nitrosamines. [33,36] The proposed re-
like growth factor-1 receptor; PLC: phospholipase C; AKT: protein
2+
kinase B; cAMP: cyclic adenosine monophosphate; PKA: protein purposing of beta-blockers and Ca -channel blockers
kinase A for lung cancer prevention would therefore inhibit
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ April 28, 2017 73