Muscarinic Receptor Agonists and Antagonists: Effects on Cancer

Spindel, Eliot R.

doi:10.1007/978-3-642-23274-9_19

Cited by 92 publications

(74 citation statements)

References 78 publications

(97 reference statements)

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“…Many studies have demonstrated that ACh mainly acts through muscarinic receptors to transduce the exo-cellular signaling and plays an critical role in tumorigeneis2829. The muscarinic receptors contained five subtypes, including M1~5 receptors.…”

Section: Discussionmentioning

confidence: 99%

Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation

Xiao

Tang

et al. 2017

Sci Rep

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Acetylcholine (ACh), known as a neurotransmitter, regulates the functions of numerous fundamental central and peripheral nervous system. Recently, emerging evidences indicate that ACh also plays an important role in tumorigenesis. However, little is known about the role of ACh in gastric cancer. Here, we reported that ACh could be auto-synthesized and released from MKN45 and BGC823 gastric cancer cells. Exogenous ACh promoted cell proliferation in a does-dependent manner. The M3R antagonist 4-DAMP, but not M1R antagonist trihexyphenidyl and M2/4 R antagonist AFDX-116, could reverse the ACh-induced cell proliferation. Moreover, ACh, via M3R, activated the EGFR signaling to induce the phosphorylation of ERK1/2 and AKT, and blocking EGFR pathway by specific inhibitor AG1478 suppressed the ACh induced cell proliferation. Furthermore, the M3R antagonist 4-DAMP and darifenacin could markedly inhibit gastric tumor formation in vivo. 4-DAMP could also significantly enhance the cytotoxic activity of 5-Fu against the MKN45 and BGC823 cells, and induce the expression of apoptosis-related proteins such as Bax and Caspase-3. Together, these findings indicated that the autocrine ACh could act through M3R and the EGFR signaling to promote gastric cancer cells proliferation, targeting M3R or EGFR may provide us a potential therapeutic strategy for gastric cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation

Xiao

Tang

et al. 2017

Sci Rep

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“…The mAChR are G-protein coupled receptors and there are 5 subtypes; M1, M3 and M5 are coupled to Gq and M2 and M4 are coupled to Gi. The majority of reports link the Gq coupled receptors to proliferation and evidence is particularly strong for a proliferative role of the M3 receptor in lung cancer and colon cancer [58–60]. M3 receptors are a particularly intriguing target since M3 muscarinic receptor antagonists are in wide clinical use for overactive bladder [61] (eg, darifenacin and solifenacin) and COPD [62] (tiotropium, aclidinium, glycopyrronium) and are generally well tolerated.…”

Section: Muscarinic Signaling In Lung Cancermentioning

confidence: 99%

Cholinergic Targets in Lung Cancer

Spindel

2016

CPD

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Background Lung cancers express an autocrine cholinergic loop in which secreted acetylcholine can stimulate tumor growth through both nicotinic and muscarinic receptors. Because activation of mAChR and nAChR stimulates growth; tumor growth can be stimulated by both locally synthesized acetylcholine as well as acetylcholine from distal sources and from nicotine in the high percentage of lung cancer patients who are smokers. The stimulation of lung cancer growth by cholinergic agonists offers many potential new targets for lung cancer therapy. Methods The potential of cholinergic targets to inhibit lung cancer growth can be evaluated by use of antagonists, agonists, gene silencing and gain of function. Results Cholinergic signaling can be targeted at the level of choline transport; acetylcholine synthesis, secretion and degradation; and nicotinic and muscarinic receptors. In addition, the newly describe family of ly-6 allosteric modulators of nicotinic signaling such as lynx1 and lynx2 offers yet another new approach to novel lung cancer therapeutics. Conclusions Each of these targets has their potential advantages and disadvantages for the development of new lung cancer therapies which are discussed in this review.

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“…Muscarinic receptors are G-protein-coupled receptors consisting of five members, CHRM1-CHRM5 (5). Activation of muscarinic receptors triggers Ca 2þ influx, which causes smooth muscle contraction and glandular secretion.…”

Section: Introductionmentioning

confidence: 99%

Autocrine Activation of CHRM3 Promotes Prostate Cancer Growth and Castration Resistance via CaM/CaMKK–Mediated Phosphorylation of Akt

Wang

Yao

et al. 2015

Clinical Cancer Research

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Purpose: Although a previous study reported nerve endingderived acetylcholine promoted prostate cancer invasion and metastasis by regulating the microenvironment of cancer cells, the present study aims to determine whether there is autocrine cholinergic signaling in prostate epithelial cells that promotes prostate cancer growth and castration resistance.Experimental design: In this study, IHC was performed to detect protein expression in mouse prostate tissue sections and human prostate cancer tissue sections. Subcutaneously and orthotopically xenografted tumor models were established to evaluate the functions of autocrine cholinergic signaling in regulating prostate cancer growth and castration resistance. Western blotting analysis was performed to assess the autocrine cholinergic signaling-induced signaling pathway.Results: We found the expression of choline acetyltransferase (ChAT), the secretion of acetylcholine and the expression of CHRM3 in prostate epithelial cells, supporting the presence of autocrine cholinergic signaling in the prostate epithelium. In addition, we found that CHRM3 was upregulated in clinical prostate cancer tissues compared with adjacent noncancer tissues. Overexpression of CHRM3 or activation of CHRM3 by carbachol promoted cell proliferation, migration, and castration resistance. On the contrary, blockading CHRM3 by shRNA or treatment with darifenacin inhibited prostate cancer growth and castration resistance both in vitro and in vivo. Furthermore, we found that autocrine cholinergic signaling caused calmodulin/calmodulin-dependent protein kinase kinase (CaM/CaMKK)-mediated phosphorylation of Akt.Conclusions: These findings suggest that blockade of CHRM3 may represent a novel adjuvant therapy for castration-resistant prostate cancer.

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Muscarinic Receptor Agonists and Antagonists: Effects on Cancer

Cited by 92 publications

References 78 publications

Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation

Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation

Cholinergic Targets in Lung Cancer

Autocrine Activation of CHRM3 Promotes Prostate Cancer Growth and Castration Resistance via CaM/CaMKK–Mediated Phosphorylation of Akt

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