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The study compared M1R and M3R expression across progressive colon neoplasia and assessed responses in three human colon cancer cell lines. Selective M1R activation reversibly inhibited proliferation, requiring receptor dependence and engaging downstream kinase pathways (EGFR, ERK1/2, p38 MAPK), without evidence for toxicity, senescence, or apoptosis involvement. 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Sundel 1,†, Natalia Sampaio Moura 2,†, Kunrong Cheng 2, Oscar Chatain 2, Shien Hu 2, Cinthia B. Drachenberg 3, Guofeng Xie 2,4,5 and Jean-Pierre Raufman 2,4,5,6, *  \nCitation: Sundel, M.H.; Sampaio Moura, N.; Cheng, K.; Chatain, O.; Hu, S.; Drachenberg, C.B.; Xie, G.; Raufman, J.-P. Selective Activation of M1 Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation. Cancers 2023, 15, 4766 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cancers15194766  \nAcademic Editors: Ming Sun, Xianghua Liu and Xuefei Shi  \nReceived: 24 August 2023  \nRevised: 20 September 2023  \nAccepted: 22 September 2023  \nPublished: 28 September 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; [maggie.sundel@som.umaryland.edu](maggie.sundel@som.umaryland.edu)  \n2 Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; [natalia.sampaiomoura@som.umaryland.edu](natalia.sampaiomoura@som.umaryland.edu) (N.S.M.); [kcheng@som.umaryland.edu](kcheng@som.umaryland.edu) (K.C.); [olchatain@liberty.edu](olchatain@liberty.edu) (O.C.); [hushien@gmail.com](hushien@gmail.com) (S.H.); [gxie@som.umaryland.edu](gxie@som.umaryland.edu) (G.X.)  \n3 Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; [cdrachenberg@som.umaryland.edu](cdrachenberg@som.umaryland.edu)  \n4 VA Maryland Healthcare System, Baltimore, MD 21201, USA  \n5 Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA  \n6 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA  \n* [Correspondence: jraufman@som.umaryland.edu](Correspondence: jraufman@som.umaryland.edu); Tel.: +1-410-328-8728 † These authors contributed equally to this work.  \nSimple Summary: M1 and M3 muscarinic receptors, M 1R and M3R, play important roles in health and disease. Previously, we found opposite patterns of expression in colon cancer for the genes encoding M 1R and M3R. Likewise, M1R and M3R deficiency had opposite effects in a mouse colon cancer model. Based on these observations, we hypothesized that activating M 1R might inhibit the growth of colon cancer cells. Here, we confirmed divergent expression of M 1R and M3R protein in progressive colon cancer. Then, we discovered that in contrast to M3R activators, treating human colon cancer cells with M1R activators inhibited cell growth. The effects of M1R activation appeared to be mediated by a signaling pathway downstream of the receptor. Notably, M 1R activation was more effective than conventional chemotherapy agents at inhibiting colon cancer cell growth and combining these agents augmented this action. We believe our findings support further investigation of selective M1R activators as treatments for advanced colon cancer.  \nAbstract: M3 muscarinic receptor (M 3R) activation stimulates colon cancer cell proliferation, migration, and invasion; M 3R expression is augmented in colon cancer and ablating M 3R expression in mice attenuates colon neoplasia. Several lines of investigation suggest that in contrast to these pro-neoplastic effects of M 3R, M1R plays an opposite role, protecting colon epithelial cells against neoplastic transformation. To pursue these intriguing findings, we examined the relative expression of M1R versus M3R in progressive stages of colon neo","cbCailmZ0Ca01ARt","https://ap.wps.com/l/cbCailmZ0Ca01ARt","pdf",1745821,"English","# Introduction\n## Receptor background and rationale\n# Abstract summary\n## Expression profiling in progressive neoplasia\n## Effects of selective M1R activation on cell proliferation\n## Mechanistic pathway analysis\n## Combination with conventional chemotherapy","[{\"question\":\"What hypothesis did the study test about M1 muscarinic receptors in colon cancer?\",\"answer\":\"The study hypothesized that activating M1R would inhibit colon cancer cell growth, contrasting with pro-neoplastic roles described for M3R.\"},{\"question\":\"How did selective M1R activation affect human colon cancer cell proliferation?\",\"answer\":\"Selective activation of M1R reversibly inhibited cell proliferation in three human colon cancer cell lines, with reduced effects when cells were pre-incubated with a selective M1R inhibitor.\"},{\"question\":\"Which signaling pathways were implicated in the observed anti-proliferative effects?\",\"answer\":\"Mechanistic experiments indicated M1R-dependent changes in activation of downstream kinases, including EGFR, ERK1/2, and p38 MAPK.\"}]","Selective Activation of M1 Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation | PDF",1790267431,48]