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

Abstract

Pancreatic cancer is the fourth leading cause of cancer deaths in developed countries. Smoking is an established risk factor for this malignancy but the underlying mechanisms are poorly understood. Previous reports have provided evidence that nicotinic acetylcholine receptors (nAChRs) and beta-adrenergic receptors (β-ARs) stimulate the growth and migration of pancreatic cancer cells. But a potential cooperation of these two receptor families in the regulation of pancreatic cancer has not been studied to date. Using two pancreatic cancer cell lines and immortalized pancreatic duct epithelia in vitro, our current data show, that all three cell lines synthesized and released the catecholamine neurotransmitters noradrenaline and adrenaline upon exposure to nicotine and that this activity was regulated by α3, α5, and α7-nAChRs. In accord with the established function of these catecholamines as β-AR agonists, nicotine-induced cell proliferation was blocked by the β-AR antagonist propranolol. Nicotine-induced proliferation was also abolished by the α7-nAChR antagonist α-bungarotoxin while catecholamine production in response to nicotine was blocked by gene knockdown of the α3, α5, and α7-nAChRs. The nicotinic agonists acetylcholine, nicotine, and its nitrosated carcinogenic derivative NNK induced the phosphorylation of CREB, ERK, Src and AKT and these responses were inhibited by propranolol. Our findings identify this hitherto unknown autocrine catecholamine loop as an important regulatory cascade in pancreatic cancer that may prove a promising new target for cancer intervention.

Nicotine Induces Tumor Growth and Chemoresistance through Activation of the PI3K/Akt/mTOR Pathway in Bladder Cancer

“…the same as previous studies on other types of cancer such as lung, breast, and pancreatic cancers (17,23,35). Moreover, our study found that increased expression of pAkt was observed within 30 minutes in a time-dependent manner at a dose of 10 mmol/L of nicotine (data not shown).…”

“…We focused on the a7-nAChR, which is highly associated with tumor growth and cancer progression in other types of cancer (23)(24)(25), and found that at least a7-nAChR was expressed in T24 cells (data not shown). As shown in Fig.…”

Interaction of the Sympathetic Nerve with Pancreatic Cancer Cells Promotes Perineural Invasion through the Activation of STAT3 Signaling

“…These promising results suggest that the sympathetic neurotransmitter NE is a bridge connecting the signaling interactions between sympathetic nerves and tumor cells by the molecules NGF and MMPs. It has been shown that pancreatic cancer cells produce their own norepinephrine and epinephrine and that both agents stimulate cell proliferation and invasion by b-adrenergic signaling in an autocrine fashion (40). Given the cross-talk between sympathetic nerves and tumor cells, it is likely that NE produced by tumor cells may be involved in PNI progression, and inhibition of the activity of sympathetic nerves may reduce the PNI in pancreatic cancer, which awaits further experimental validation.…”

A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response

“…Furthermore, work from Al-Wadei and colleagues demonstrated that stimulation of normal pancreatic duct epithelial cells by nicotine could induce production of catecholamines [41]. Activation of adrenergic receptors by autocrine signaling on non-transformed cells resulted in increased cell proliferation and activation of oncogenic proteins including epithelial growth factor receptor (EGFR).…”