Muscarinic receptors and ligands in cancer

Abstract

Emerging evidence indicates that muscarinic receptors and ligands play key roles in regulating cellular proliferation and cancer progression. Both neuronal and nonneuronal acetylcholine production results in neurocrine, paracrine, and autocrine promotion of cell proliferation, apoptosis, migration, and other features critical for cancer cell survival and spread. The present review comprises a focused critical analysis of evidence supporting the role of muscarinic receptors and ligands in cancer. Criteria are proposed to validate the biological importance of muscarinic receptor expression, activation, and postreceptor signaling. Likewise, criteria are proposed to validate the role of nonneuronal acetylcholine production in cancer. Dissecting cellular mechanisms necessary for muscarinic receptor activation as well as those needed for acetylcholine production and release will identify multiple novel targets for cancer therapy.

M2muscarinic receptors inhibit cell proliferation and migration in urothelial bladder cancer cells

“…In fact, in non-neuronal tissues such as bladder, the acetylcholine could be released in an autocrine or paracrine fashion, modulating the functions of the neighbouring cells. 32 In addition, in pathological conditions including cancer, an altered sensitivity of tumor cells to muscarinic receptors has been described. 33,34 Both these aforementioned explanations need further experiments to elucidate the biological function of M2 muscarinic receptors in bladder cancer.…”

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

“…Recently neurotransmitters and their ligands have been reported to regulate the proliferation, apoptosis and metastasis of many cancers and cancer-related angiogenesis [31,32]; small cell lung carcinoma [27] and squamous cell lung carcinoma [33] express AchRs with choline acetyltransferase and while in lung adenocarcinoma, β 1 -and β 2 -ADR [34]. This neurotransmitter-mediated proliferation is regulated via activation of ERK1/2 (phosphorylation of MAPK) [32,35].…”

GPCRs and cancer

“…As for β-adrenergic compounds [156] , the action of muscarinic acetylcholine receptors (mAchRs) on the proliferation of cancer cells is still questioned [157] . In fact, these receptors interact with distinct G protein subunits triggering various cellular functions through specific downstream effectors.…”

“…These mAchR subtypes can protect cells from the apoptosis subsequent to DNA damage, oxidative stress and mitochondrial dysfunction [158] . Although muscarinic receptor expression was identified in cells derived from brain, breast, colon, lung, ovary, pancreas, prostate, skin, stomach and uterus malignancies [157] , only for some of these receptors a functional role has been demonstrated. In ovarian cancer the expression of muscarinic receptors was associated with reduced survival [159] , while in leukemia cells their activation resulted in increased intracellular calcium and upregulation of the oncogene c-fos [160] .…”

“…In ovarian cancer the expression of muscarinic receptors was associated with reduced survival [159] , while in leukemia cells their activation resulted in increased intracellular calcium and upregulation of the oncogene c-fos [160] . Activation of M3 receptor by cholinergic agonists stimulated proliferation of primary astrocytoma cells in a ERK and NF-κB dependent manner [157] . In breast cancer cells, M1 and M2 receptors were involved in angiogenesis and cell proliferation, whereas M3 receptor was associated only with cell growth [161] .…”