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Cancers 2019, 11(3), 308; https://doi.org/10.3390/cancers11030308

The Role of M3 Muscarinic Receptor Ligand-Induced Kinase Signaling in Colon Cancer Progression

1
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
2
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
3
Department of Medicine, University of Maryland School of Medicine and VA Maryland Health Care System, Baltimore, MD 21201, USA
*
Author to whom correspondence should be addressed.
Received: 7 February 2019 / Revised: 22 February 2019 / Accepted: 27 February 2019 / Published: 5 March 2019
(This article belongs to the Special Issue Protein Kinases and Cancers)
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Abstract

Despite a reduction in incidence over the past decade, colon cancer remains the second most common cause of cancer death in the United States; recent demographics suggest this disease is now afflicting younger persons. M3 muscarinic receptor (M3R) mRNA and protein are over-expressed in colon cancer, and M3R can be activated by both traditional (e.g., acetylcholine) and non-traditional (e.g., bile acids) muscarinic ligands. In this review, we weigh the data supporting a prominent role for key protein kinases downstream of M3R activation in promoting colon cancer progression and dissemination. Specifically, we explore the roles that downstream activation of the mitogen activated protein kinase/extracellular signal-related kinase (MAPK/ERK), protein kinase C, p38 MAPK, and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathways play in mediating colon cancer cell proliferation, survival, migration and invasion. We assess the impact of M3R-stimulated induction of selected matrix metalloproteinases germane to these hallmarks of colon cancer progression. In this context, we also critically review the reproducibility of findings derived from a variety of in vivo and in vitro colon cancer models, and their fidelity to human disease. Finally, we summarize the therapeutic potential of targeting various steps from ligand-M3R interaction to the activation of key downstream molecules. View Full-Text
Keywords: muscarinic ligands; muscarinic receptors; colon cancer; bile acids; acetylcholine muscarinic ligands; muscarinic receptors; colon cancer; bile acids; acetylcholine
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Tolaymat, M.; Larabee, S.M.; Hu, S.; Xie, G.; Raufman, J.-P. The Role of M3 Muscarinic Receptor Ligand-Induced Kinase Signaling in Colon Cancer Progression. Cancers 2019, 11, 308.

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