Development of Novel Therapeutic Strategies for Lung Cancer: Targeting the Cholinergic System

Abstract

One of the earliest descriptions of non-neuronal ACh synthesis was by Morris who reported that ACh was synthesized in the placenta [1]; furthermore, Falugi et al. showed the presence of AChE in human fibrosarcoma cells [2]. Afterward, the expression of ACh, AChE, and cholinergic receptors in non-neuronal cells was reported in several studies [3-16]. Indeed, recent data reported that SCLC expresses a cholinergic autocrine loop that can regulate cell growth. Such work demonstrates that SCLC cells have a cholinergic phenotype and that ACh exerts as an autocrine growth factor in human lung tumours [16]. Moreover, it has been recently reported that nicotine in lung adenocarcinoma A549 cells, potently induces Bad phosphorylation at serine (S)112, S136 and S155 in a mechanism involving activation of MAPKs, ERK1/2, PI3K/AKT and PKA through the linking to alpha7-receptors [9]. Bad phosphorylation results in sequestering Bad from mitochondria and subsequently interacting with 14-3-3 in the cytosol [9]. We have recently reported that human malignant pleural mesothelioma expresses a cholinergic system, involved in cell growth regulation. Hence, mesothelioma cells growth is modulated by the cholinergic system in which agonists (i.e. nicotine) have a proliferative effect and antagonists (i.e. curare or alpha-cobratoxin) have an inhibitory effect. Furthermore apoptosis mechanisms are under the control of the cholinergic system (nicotine antiapoptotic via induction of NF-kappaB complexes and phosphorylation of Bad at S112, curare proapoptotic via G0-G1 arrest p21waf-1-dependent, but p53-independent) [16]. The involvement of the non-neuronal cholinergic system in lung cancer and mesothelioma appears reasonable and opens up new translational research strategies.

Retracted: Inhibition of non‐neuronal α7‐nicotinic receptor reduces tumorigenicity in A549 NSCLC xenografts

“…16 The animal venom toxins antagonists of AChR [i.e., bungarotoxin (BTX) from the Bungarus multicinctus snake and conotoxins purified from the venom of Conus marine snails] have previously been used as molecular tools for the characterization of neuronal nAChR in SCLC, NSCLC and mesothelioma or for inhibiting nicotine action. A latest study 35 showed that a-BTX inhibits the proliferation of human bronchial BEP2D cells exposed to NNK This work is devoted to the memory of Dr. Andr e M enez, President of the French Natural History Museum, and a world-renowned expert in the molecular and structural biology of animal toxins.…”

“…[5][6][7][8][9][10][11][12][13][14][15] The primary functions of non-neuronal ACh might involve it in cell-to-cell communication mediated by intracellular ion dynamics, linked to the regulation of a number of events, such as cell motility, responses to the cellular environment and apoptosis. 6,[16][17][18][19][20] Moreover, the discovery of functional acetylcholine receptors (AChR) on lung epithelial cells and lung tumors raises the question of whether exposure to nicotine could also participate in lung cancer pathogenesis by activating signal transduction pathways, such as the Akt pathway, and/or overcome apoptotic responses engendered by carcinogen exposure. [16][17][18][19][20] It has been largely demonstrated that nicotine stimulates the proliferation of human small cell lung cancer (SCLC) cells by binding the a7-nicotinic acetylcholine receptors (nAChR), resulting in the release of 5-HT.…”

Novel and Extensive Aspects of Paraquat-Induced Pulmonary Fibrogenesis: Comparative and Time-Course Microarray Analyses in Fibrogenic and Non-Fibrogenic Rats

“…Moreover, it has been recently reported that nicotine potently induces Bad phosphorylation through linkage with a nicotinic acetylcholine receptor subunit, α7-nAChR (Chna7). Chna7 is involved in the regulation of cell proliferation or apoptosis in the lung (Dasgupta et al, 2006;Jin et al, 2004;Russo et al, 2006;Schuller et al, 2000). Bad is a pro-apoptotic factor, but phosphorylation of Bad has been demonstrated to inactivate its pro-apoptotic function.…”

Nicotine Addiction: Role of the Nicotinic Acetylcholine Receptors Genetic Variability in Knowledge, Prevention and Treatment

“…nAChR are acetylcholine gated ion channels consisting of homo-or heteropentamers subunits arranged symmetrically around a membrane perpendicular axis, outlining the ionic hole (Russo et al, 2006;Taly et al, 2009) (Fig. 2.).…”

“…The homomeric 7 nAChR is a special case, since having five agonist-binding sites per receptor can bind from two to five molecules of agonist. 7-nAChR utilizes multiple calcium amplification pathways to efficiently raise the intracellular calcium levels by subsequent activation of voltage-gated calcium channels as well as calcium release from the endoplasmic reticulum (Russo et al, 2006;Taly et al, 2009). …”