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

Abstract

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.

Figure 1

The stress neurotransmitters norepinephrine and epinephrine are the physiological agonists for β-ARs. Both agents bind to α and β-ARs, with norepinephrine having higher affinity for the β1-AR and epinephrine for the β2-AR. They each contain a catechol ring and an aliphatic side chain with a nitrogen atom. When the steric bulk of the side chain is increased (as in isoproterenol), the ligand binds selectively to β-ARs. The pyridine ring of the nicotine-derived carcinogenic nitrosamine NNK with its aliphatic side chain containing the N-Nitroso group (N-N=O) resembles isoproterenol, rendering the affinity of NNK 2,200 times greater than epinephrine to the β2-AR and 600 times greater than norepinephrine to the β1-AR [19, 20].

Figure 2

Photomicrographs exemplifying immunostains for the expression of the b1-and b2-AR in lung adenocarcinoma tissues on tissue microarray LC1002 (Biomax Inc., Rockville, MD, USA), containing 48 cases of lung adenocarcinoma. Each of these cases showed prominent expression of the β1-AR whereas only faint positive immunoreactivity was detected for the β2-AR. Immunostains were conducted using a Vectastain ABC kit (Vector Laboratories, Burlingame, CA, USA) with exposure to primary antibodies (Santa Cruz Biotechnologies, Santa Cruz, CA, USA) at a dilution of 1: 25 overnight in a moist chamber at 4°C.

Figure 3

Working model of the direct effects of NNK on cancer promoting beta-adrenergic signaling in pulmonary adenocarcinoma and pancreatic ductal adenocarcinoma. Binding of NNK to the β1-and β2-ARs activates the stimulatory G-protein Gα_s, leading to the activation of adenylyl cyclase, the single rate-limiting step for the formation of cAMP from ATP. In turn, cAMP and its effector activated PKA activate multiple intracellular signaling cascades that have been shown to increase cell proliferation, migration and angiogenesis while inhibiting apoptosis in PAC and PDAC. This entire cancer-promoting cascade is successfully interrupted by beta-blockers that prevent binding of NNK to β-ARs or by GABA that inhibits the activation of adenylyl cyclase.

Figure 4

The tobacco constituents nicotine and NNK as well as psychological stress cause the release of the stress neurotransmitters norepinephrine and epinephrine from sympathetic nerves and from the adrenal medulla into the systemic circulation [9, 48]. In addition, they stimulate the synthesis and release of both stress neurotransmitters from small airway epithelial cells and from pancreatic duct epithelium, in which these agents act as autocrine growth factors [16, 17].

Figure 5

Working model of the indirect effects of chronic psychological stress, chronic NNK and nicotine on cancer promoting beta-adrenergic signaling via nicotinic receptor-mediated synthesis and release of stress neurotransmitters and suppression of GABA. Responses to psychological stress are initiated by binding of the neurotransmitter acetylcholine to nAChRs whereas nicotine and NNK in smokers replace acetylcholine as nAChR ligands due to their higher affinity to these receptors. Upon chronic exposure to either of these agonists, protein expression of nAChRs α7, α5, and α3 is increased without concomitant desensitization, causing increased synthesis and release of norepinephrine and epinephrine that drive cancer promoting beta-adrenergic signaling. By contrast, the same nAChR agonists desensitize the α4β2nAChR and despite of its reactive increase in receptor protein synthesis and release of its effector GABA is suppressed. Promoter hypermethylation of the enzyme glutamate decarboxylase (GAD), which catalyzes the formation of GABA from glutamate, additionally suppresses GABA synthesis. The resulting hyperactive cAMP-dependent signaling downstream of β-ARs can be reduced to physiological levels by beta-blockers, GABA supplementation of positive psychological influences, such as happiness.