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Selective Activation of M(1) Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation

SIMPLE SUMMARY: M(1) and M(3) muscarinic receptors, M(1)R and M(3)R, play important roles in health and disease. Previously, we found opposite patterns of expression in colon cancer for the genes encoding M(1)R and M(3)R. Likewise, M(1)R and M(3)R deficiency had opposite effects in a mouse colon can...

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Autores principales: Sundel, Margaret H., Sampaio Moura, Natalia, Cheng, Kunrong, Chatain, Oscar, Hu, Shien, Drachenberg, Cinthia B., Xie, Guofeng, Raufman, Jean-Pierre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10571583/
https://www.ncbi.nlm.nih.gov/pubmed/37835460
http://dx.doi.org/10.3390/cancers15194766
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author Sundel, Margaret H.
Sampaio Moura, Natalia
Cheng, Kunrong
Chatain, Oscar
Hu, Shien
Drachenberg, Cinthia B.
Xie, Guofeng
Raufman, Jean-Pierre
author_facet Sundel, Margaret H.
Sampaio Moura, Natalia
Cheng, Kunrong
Chatain, Oscar
Hu, Shien
Drachenberg, Cinthia B.
Xie, Guofeng
Raufman, Jean-Pierre
author_sort Sundel, Margaret H.
collection PubMed
description SIMPLE SUMMARY: M(1) and M(3) muscarinic receptors, M(1)R and M(3)R, play important roles in health and disease. Previously, we found opposite patterns of expression in colon cancer for the genes encoding M(1)R and M(3)R. Likewise, M(1)R and M(3)R deficiency had opposite effects in a mouse colon cancer model. Based on these observations, we hypothesized that activating M(1)R might inhibit the growth of colon cancer cells. Here, we confirmed divergent expression of M(1)R and M(3)R protein in progressive colon cancer. Then, we discovered that in contrast to M(3)R activators, treating human colon cancer cells with M(1)R activators inhibited cell growth. The effects of M(1)R activation appeared to be mediated by a signaling pathway downstream of the receptor. Notably, M(1)R 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 M(1)R activators as treatments for advanced colon cancer. ABSTRACT: M(3) muscarinic receptor (M(3)R) activation stimulates colon cancer cell proliferation, migration, and invasion; M(3)R expression is augmented in colon cancer and ablating M(3)R expression in mice attenuates colon neoplasia. Several lines of investigation suggest that in contrast to these pro-neoplastic effects of M(3)R, M(1)R plays an opposite role, protecting colon epithelial cells against neoplastic transformation. To pursue these intriguing findings, we examined the relative expression of M(1)R versus M(3)R in progressive stages of colon neoplasia and the effect of treating colon cancer cells with selective M(1)R agonists. We detected divergent expression of M(1)R and M(3)R in progressive colon neoplasia, from aberrant crypt foci to adenomas, primary colon cancers, and colon cancer metastases. Treating three human colon cancer cell lines with two selective M(1)R agonists, we found that in contrast to the effects of M(3)R activation, selective activation of M(1)R reversibly inhibited cell proliferation. Moreover, these effects were diminished by pre-incubating cells with a selective M(1)R inhibitor. Mechanistic insights were gained using selective chemical inhibitors of post-muscarinic receptor signaling molecules and immunoblotting to demonstrate M(1)R-dependent changes in the activation (phosphorylation) of key downstream kinases, EGFR, ERK1/2, and p38 MAPK. We did not detect a role for drug toxicity, cellular senescence, or apoptosis in mediating M(1)R agonist-induced attenuated cell proliferation. Lastly, adding M(1)R-selective agonists to colon cancer cells augmented the anti-proliferative effects of conventional chemotherapeutic agents. Collectively, these results suggest that selective M(1)R agonism for advanced colon cancer, alone or in combination with conventional chemotherapy, is a therapeutic strategy worth exploring.
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spelling pubmed-105715832023-10-14 Selective Activation of M(1) Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation Sundel, Margaret H. Sampaio Moura, Natalia Cheng, Kunrong Chatain, Oscar Hu, Shien Drachenberg, Cinthia B. Xie, Guofeng Raufman, Jean-Pierre Cancers (Basel) Article SIMPLE SUMMARY: M(1) and M(3) muscarinic receptors, M(1)R and M(3)R, play important roles in health and disease. Previously, we found opposite patterns of expression in colon cancer for the genes encoding M(1)R and M(3)R. Likewise, M(1)R and M(3)R deficiency had opposite effects in a mouse colon cancer model. Based on these observations, we hypothesized that activating M(1)R might inhibit the growth of colon cancer cells. Here, we confirmed divergent expression of M(1)R and M(3)R protein in progressive colon cancer. Then, we discovered that in contrast to M(3)R activators, treating human colon cancer cells with M(1)R activators inhibited cell growth. The effects of M(1)R activation appeared to be mediated by a signaling pathway downstream of the receptor. Notably, M(1)R 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 M(1)R activators as treatments for advanced colon cancer. ABSTRACT: M(3) muscarinic receptor (M(3)R) activation stimulates colon cancer cell proliferation, migration, and invasion; M(3)R expression is augmented in colon cancer and ablating M(3)R expression in mice attenuates colon neoplasia. Several lines of investigation suggest that in contrast to these pro-neoplastic effects of M(3)R, M(1)R plays an opposite role, protecting colon epithelial cells against neoplastic transformation. To pursue these intriguing findings, we examined the relative expression of M(1)R versus M(3)R in progressive stages of colon neoplasia and the effect of treating colon cancer cells with selective M(1)R agonists. We detected divergent expression of M(1)R and M(3)R in progressive colon neoplasia, from aberrant crypt foci to adenomas, primary colon cancers, and colon cancer metastases. Treating three human colon cancer cell lines with two selective M(1)R agonists, we found that in contrast to the effects of M(3)R activation, selective activation of M(1)R reversibly inhibited cell proliferation. Moreover, these effects were diminished by pre-incubating cells with a selective M(1)R inhibitor. Mechanistic insights were gained using selective chemical inhibitors of post-muscarinic receptor signaling molecules and immunoblotting to demonstrate M(1)R-dependent changes in the activation (phosphorylation) of key downstream kinases, EGFR, ERK1/2, and p38 MAPK. We did not detect a role for drug toxicity, cellular senescence, or apoptosis in mediating M(1)R agonist-induced attenuated cell proliferation. Lastly, adding M(1)R-selective agonists to colon cancer cells augmented the anti-proliferative effects of conventional chemotherapeutic agents. Collectively, these results suggest that selective M(1)R agonism for advanced colon cancer, alone or in combination with conventional chemotherapy, is a therapeutic strategy worth exploring. MDPI 2023-09-28 /pmc/articles/PMC10571583/ /pubmed/37835460 http://dx.doi.org/10.3390/cancers15194766 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sundel, Margaret H.
Sampaio Moura, Natalia
Cheng, Kunrong
Chatain, Oscar
Hu, Shien
Drachenberg, Cinthia B.
Xie, Guofeng
Raufman, Jean-Pierre
Selective Activation of M(1) Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation
title Selective Activation of M(1) Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation
title_full Selective Activation of M(1) Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation
title_fullStr Selective Activation of M(1) Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation
title_full_unstemmed Selective Activation of M(1) Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation
title_short Selective Activation of M(1) Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation
title_sort selective activation of m(1) muscarinic receptors attenuates human colon cancer cell proliferation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10571583/
https://www.ncbi.nlm.nih.gov/pubmed/37835460
http://dx.doi.org/10.3390/cancers15194766
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