Nicotine stimulates pancreatic cancer xenografts by systemic increase in stress neurotransmitters and suppression of the inhibitory neurotransmitter  -aminobutyric acid

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality in Western countries. We have shown previously that four representative human PDAC cell lines were regulated by beta-adrenoreceptors via cyclic adenosine 3',5'-monophosphate (cAMP)-dependent signaling. In the current study, we have tested the hypothesis that nicotine stimulates the growth of PDAC xenografts in nude mice by increasing the systemic levels of the stress neurotransmitters adrenaline and noradrenaline, which are the physiological agonists for beta-adrenoreceptors and that inhibition by gamma-aminobutyric acid (GABA) of the adenylyl cyclase-dependent pathway downstream of adrenoreceptors blocks this effect. The size of xenografts from PDAC cell line Panc-1 was determined 30 days after inoculation of the cancer cells. Stress neurotransmitters in serum as well as cAMP in the cellular fraction of blood and in tumor tissue were assessed by immunoassays. Levels of GABA, its synthesizing enzymes GAD65 and GAD67 and beta-adrenergic signaling proteins in the tumor tissue were determined by western blotting. Nicotine significantly increased the systemic levels of adrenaline, noradrenaline and cAMP while increasing xenograft size and protein levels of cAMP, cyclic AMP response element-binding protein and p-extracellular signal-regulated kinase 1/2 in the tumor tissue. Nicotine additionally reduced the protein levels of both GAD isozymes and GABA in tumor tissue. Treatment with GABA abolished these responses to nicotine and blocked the development of xenografts in mice not exposed to nicotine. These findings suggest that the development and progression of PDAC is subject to significant modulation by stimulatory stress neurotransmitters and inhibitory GABA and that treatment with GABA may be useful for marker-guided cancer intervention of PDAC.

Chronic stress accelerates pancreatic cancer growth and invasion: A critical role for beta-adrenergic signaling in the pancreatic microenvironment

“…In contrast, interpretation of previous studies that investigated pancreatic tumor growth in flank was limited by the context of non-physiological intercellular interactions [55–58]. To better understand β-adrenergic regulation of pancreatic cancer onset it will be important to investigate the effects of chronic stress in transgenic models that spontaneously develop pancreatic cancer [59].…”

Pancreatic Cancer Cells and Normal Pancreatic Duct Epithelial Cells Express an Autocrine Catecholamine Loop that Is Activated by Nicotinic Acetylcholine Receptors α3, α5, and α7

“…Accordingly, a previous study by our laboratory showed a significant nicotine-induced growth promotion of pancreatic cancer xenografts associated with increased levels of noradrenaline, adrenaline and cAMP in blood and xenograft tissues as well as an induction of p-CREB and p-ERK in xenograft tissues. These changes were interpreted as indirect effects of such systemic neuroendocrine responses (28). Our current in vitro experiments are not influenced by this systemic neuroendocrine effect of nicotine and unequivocally show that two pancreatic cancer cell lines as well as immortalized pancreatic duct epithelia synthesized and released their own noradrenaline and adrenaline in response to nicotine.…”

“…In addition, it has been shown that γ-aminobutyric acid (GABA) inhibited the proliferation and migration of pancreatic cancer cells in vitro via GABA-B receptor mediated inhibition of adenylyl cyclase (20). GABA also reversed the growth promoting effects of nicotine on pancreatic cancer xenografts by reducing tumor cAMP levels (28). GABA has been safely used as a nutritional supplement for many years and selective GABA-B-receptor agonists are widely used for the pharmacological management of spastic pain after spinal injuries and spinal surgery.…”

Prevention of pancreatic cancer in a hamster model by cAMP decrease

“…Gene-knockdown of Gα i -coupled GABA-B receptors (GABA-B-Rs) blocked these effects of GABA while transient overexpression of GABA-B-Rs enhanced these responses to GABA, identifying the Gα i -mediated inhibition of adenylate cyclase activation as the underlying mechanism [11]. In accord with these in vitro findings, the progression of PDAC xenografts in athymic nude mice was significantly inhibited in the absence and presence of chronic exposure to nicotine or social stress by treatment of the animals with GABA in the drinking water [12, 24]. GABA treatment also enhanced the responsiveness of PDAC xenografts to the cancer therapeutic agent celecoxib in the absence and presence of social stress [25].…”