M3 Muscarinic Receptor Antagonists Inhibit Small Cell Lung Carcinoma Growth and Mitogen-Activated Protein Kinase Phosphorylation Induced by Acetylcholine Secretion

Abstract

The importance of acetylcholine as a neurotransmitter in the nervous system is well established, but little is yet known about its recently described role as an autocrine and paracrine hormone in a wide variety of nonneuronal cells. Consistent with the expression of acetylcholine in normal lung, small cell lung carcinoma (SCLC) synthesize and secrete acetylcholine, which acts as an autocrine growth factor through both nicotinic and muscarinic cholinergic mechanisms. The purpose of this study was to determine if interruption of autocrine muscarinic cholinergic signaling has potential to inhibit SCLC growth. Muscarinic receptor (mAChR) agonists caused concentration-dependent increases in intracellular calcium and mitogen-activated protein kinase (MAPK) and Akt phosphorylation in SCLC cell lines. The inhibitory potency of mAChR subtype-selective antagonists and small interfering RNAs (siRNAs) on acetylcholine-increased intracellular calcium and MAPK and Akt phosphorylation was consistent with mediation by M3 mAChR (M3R). Consistent with autocrine acetylcholine secretion stimulating MAPK and Akt phosphorylation, M3R antagonists and M3R siRNAs alone also caused a decrease in basal levels of MAPK and Akt phosphorylation in SCLC cell lines. Treatment of SCLC cells with M3R antagonists inhibited cell growth both in vitro and in vivo and also decreased MAPK phosphorylation in tumors in nude mice in vivo. Immunohistochemical staining of SCLC and additional cancer types showed frequent coexpression of acetylcholine and M3R. These findings suggest that M3R antagonists may be useful adjuvants for treatment of SCLC and, potentially, other cancers. [Cancer Res 2007;67(8):3936-44]

Blocking M2 muscarinic receptor signaling inhibits tumor growth and reverses epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC)

“…It has been reported that cholinergic stimulation leads to cell proliferation through MAPK and Akt pathways. 27,33 In this study, in parallel with stimulation of A549 and PC9 cell proliferation by either carbachol or pilocarpine, phosphorylation of MAPK and Akt was increased ( Fig. S2 and S3).…”

“…26 In SCLC, tumor growth has been associated with stimulation of M3 mAChR through mitogen-activated protein kinase (MAPK)-dependent mechanisms. 27 M3 mAChR antagonists can inhibit SCLC growth in vitro and in vivo. In NSCLC, very little is known about which subtypes mediate the proliferative effects of muscarinic activation.…”

Constitutively Active Soluble Form of Erythropoietin Receptor Suppresses Growth and Angiogenesis of Xenografts of Transfected Cancer Cell Lines

“…Recently chronic stress and other behavioral conditions have been reported to cause promotion and progression of cancers; catecholamines in ovarian cancers [21,22], muscarinic cholinergic receptors in prostate [23], colon [24], mammary carcinoma cells [25,26], and the receptors and ligands in small cell lung carcinoma [27,28] were shown to promote their growth and angiogenesis.…”

CHRNA7 inhibits cell invasion and metastasis of LoVo human colorectal cancer cells through PI3K/Akt signaling

“…Vukelic et al showed that cholinergic neurotransmitters (ACh), similar to those released through activation of a neural reflex, regulate responses to products of the adaptive immune system, specifically immune complex (IC)-mediated activation of effector cells (31). In particular, in both lung cancer and colon cancer, ACh acts as an autocrine growth factor for cancer growth and development (32)(33)(34). Since cancer cells both produce ACh and express nAChRs, these receptors are believed to be involved in tumorigenesis, even without stimulation with nicotine.…”