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

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.

Overcoming Obstacles to Targeting Muscarinic Receptor Signaling in Colorectal Cancer

“…For proof-of-principle, Rosenvinge et al demonstrated that conditioned media from pheochromocytoma cells can stimulate the proliferation of H508 colon cancer cells, an action blocked by pretreating cells with the muscarinic receptor antagonist atropine [ 60 ]. These findings are consistent with the hypothesis that ACh released from the neuroendocrine tumor stimulated swift regrowth of remnant cells after endoscopic resection of the rectal cancer [ 59 , 60 ].…”

“…These biological phenomena may have clinical consequences. Pheochromocytomas, uncommon neuroendocrine tumors that secrete excess catecholamines, may also produce excess ACh [ 58 , 59 ]. Despite previous endoscopic resection of a small focus of rectal cancer and vigilant surveillance, an elderly man with an unresectable pheochromocytoma experienced rapid recurrence of the rectal adenocarcinoma [ 60 ].…”

M3 receptor modulates extracellular matrix synthesis via ERK1/2 signaling pathway in human bladder smooth muscle cells

“…Muscarinic receptors are comprised of five subtypes, M 1 ‐M 5 , which are encoded in the bladder detrusor muscle cells 10,11 . They are reported to regulate diverse cellular functions, excessive stimulation of which can result in deterioration of many disorders, such as COPD, cognitive impairment, colon cancer 12‐14 . In human lung fibroblasts, Haag et al 15 have found that the muscarinic receptor agonist CCH could significantly increase collagen synthesis.…”

Role of Muscarinic Acetylcholine Signaling in Gastrointestinal Cancers

“…Collectively, these findings support important roles for M3R expression and activation in the progression of colon neoplasia [67]. M3R and its downstream signaling pathway may be a promising therapeutic target of colon cancer [68].…”