Page 80 - Read Online

Schuller Neurotransmitter receptors and cancer

progression and metastasis of numerous cancers. acetylcholine and are also able to synthesize and
[31]
The neurotransmitters of the sympathetic branch of release Nor and Epi in response to acetylcholine
the autonomic nervous system, epinephrine (Epi) and self-stimulation or exposure to exogenous nAChR
norepinephrine (Nor) are the physiological agonists for agonists. [32-36] In addition, it has been shown that
β-ARs. Epi and Nor are additionally synthesized and polymorphisms in genes CHRNA3 (encodes the
released by the adrenal medulla and are often referred α3 nAChR subunit) and CHRNA5 (encodes the α5
to as “stress neurotransmitters” because psychological nAChR subunit) as well as a copy number variation
stress triggers their simultaneous release from the that duplicates the α7nAChR gene CHRNA7 are
sympathetic nervous system and adrenal gland. [10,11] associated with an increased risk for lung cancer [37-39]
The release of stress neurotransmitters from the and that single nucleotide polymorphisms in the β2-AR
sympathetic nervous system and adrenal gland is gene are associated with adverse clinical outcomes of
regulated by nAChRs via Ca influx that triggers their pancreatic cancer. [40]
2+
exocytosis. [12,13] The biology of β-ARs as it relates
to cardio-vascular disease has been extensively An important aspect of cancer regulation by
studied and beta-adrenergic receptor antagonists neurotransmitters and their receptors is the significant
(beta-blockers) and VOC blockers are widely used as influence of the mood on this regulatory network
therapeutics for this disease complex. [14-17] [Figure 1]. Preclinical investigations have thus
shown that experimentally induced psychological
Discoveries that nicotine induced the proliferation stress or treatment with stress neurotransmitters
of human small cell lung cancer cells in vitro while have strong promoting effects on the majority of the
[18]
inhibiting apoptosis, effects triggered by the nAChR- most common human cancers via direct activation
[19]
mediated release and re-uptake of the neurotransmitter of cAMP-dependent intracellular signaling pathways
5-hydroxytryptamine (5-HT, serotonin), first pointed by stress neurotransmitters downstream of β1 and
[20]
to nAChRs as important regulators of a subset of β2-ARs [29,32,41-45] and the simultaneous suppression
cancers. Reports that β-AR agonists stimulated the of the tumor suppressor gene p53 by beta-arrestin-1
proliferation of lung adenocarcinoma cells in vitro and signaling downstream of β2-ARs. Moreover, chronic
[46]
that this response was inhibited by β-blockers first experimental stress suppressed the synthesis and
implicated β-ARs in the regulation of another subset release of the inhibitory neurotransmitter γ-aminobutyric
of cancers. [21,22] The identification of the tobacco acid (GABA). [41,42] These findings are in accord with the
carcinogen nicotine-derived nitrosamine ketone (NNK) reported suppression of the GABA system by chronic
as a high affinity agonist for nAChRs [23,24] as well as psychological stress and in anxiety disorders such
[47]
β-ARs subsequently provided a direct mechanistic link as posttraumatic stress syndrome. [48,49] GABA is the
[7]
between the high carcinogenic potential of this agent main inhibitory neurotransmitter in the mammalian
and its interaction with neurotransmitter receptors. body and inhibits the AC-dependent formation of
These studies also showed that NNK-induced β-AR cAMP as well as the activation of voltage-gated Ca 2+-
signaling in lung adenocarcinoma cells and pancreatic channels under physiological conditions by activating
[50]
ductal adenocarcinoma cells triggered the release of inhibitory G-protein (G) signaling downstream of G- i
i
AA, resulting in the formation of cancer-stimulating coupled GABA-B-receptors. In light of findings that
AA metabolites while additionally trans-activating the GABA-B receptor has tumor suppressor function
the epidermal growth factor receptor pathway. [7,8,25] in pancreatic [42,51-53] and non small-cell lung cancer
Collectively, these early findings represented the (NSCLC) [35,41,54,55] while GABA also inhibits the in
starting point for a new domain in cancer research: vitro growth of breast cancer and colon cancer, [47,56]
the role of neurotransmitters and their receptors in suppression of GABA by psychological stress has
the initiation, progression and drug resistance of significant tumor promoting effects on these cancers.
cancer and the development of novel therapeutic
and preventive strategies that target this regulatory Similar to chronic stress, smoking also increases the
network. [26-30] levels of cancer stimulating stress neurotransmitters
[57]
while suppressing cancer inhibiting GABA, effects
[2]
It was initially thought that nAChRs and β-ARs caused by the neuroadaptation of nAChRs to chronic
expressed in non-neuronal cells and cancers nicotine, NNK and N’-nitrosonornicotine (NNN). In
derived from them were exclusively stimulated by the conjunction with the mutational activities of NNK and
autonomic nervous system or by exposure to tobacco NNN at the K-ras and p53 genes, the resulting
[58]
products. However, more recent studies have shown prevalence of cancer stimulating beta-adrenergic
that numerous non-neuronal cells and the cancers receptor signaling contributes significantly to the
derived from them synthesize and release their own increased cancer risk of smokers.
72 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ April 28, 2017