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Muscarinic receptor signaling and colon cancer progression

Guofeng Xie, Jean-Pierre Raufman
Division of Gastroenterology and Hepatology, Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine,
Baltimore, MD 21201, USA.
Correspondence to: Dr. Guofeng Xie, Division of Gastroenterology and Hepatology, Veterans Affairs Maryland Health Care System, University
of Maryland School of Medicine, 22 South Greene St., Baltimore, MD 21201, USA. E-mail: gxie@medicine.umaryland.edu

A B S T R AC T
Due to the lack of effective treatments, advanced colorectal cancer (CRC) remains a leading cause of cancer death in the
United States. Emerging evidence supports the observation that muscarinic receptor (MR) signaling plays a critical role in
growth and progression of CRC. MR activation by acetylcholine and bile acids results in transactivation of epidermal growth
factor receptors (EGFR) and post-EGFR signal transduction that enhances cell proliferation, migration, and invasion. Here, the
authors review recent progress in understanding the molecular mechanisms underlying MR-mediated CRC progression and its
therapeutic implications.

Key words: Muscarinic receptor; colon cancer; epidermal growth factor receptors; bile acids; acetylcholine

INTRODUCTION advanced CRC remains only 10-15%. [4,5] New therapeutic
approaches are urgently needed.
Colorectal cancer (CRC) is the second leading cause of
cancer death worldwide with 1.4 million new cases and MUSCARINIC RECEPTORS IN NORMAL
693,900 deaths each year. In the United States, CRC is COLON TISSUE AND CRC
[1]
currently the third leading cause of cancer death for both
men and women. [2,3] Annually, approximately 140,000 The muscarinic cholinergic family of G-protein-coupled
people are diagnosed with CRC of which 50,000 will die, receptors (GPCRs) consists of five muscarinic receptor
primarily from advanced disease. [2,3] Although surgical and (MR) subtypes designated muscarinic acetylcholine
endoscopic treatment is very effective for patients with receptor subtype M1 (M1R)-M5R (for review see [6-9] ).
early-stage CRC, late-stage CRC is generally resistant to MR is expressed in many tissue types and play important
chemo- and radiation- therapy. roles in progression of many cancers including breast,
prostate, lung and CRC. [10-12] M1R and M3R, expressed
Uncontrolled cell proliferation is an integral part of widely in the gastrointestinal (GI) tract, are coupled to
CRC progression. Cancer cell proliferation is regulated G , activate phospholipase C and increase cell calcium.
q11
by a variety of growth factors and receptors. Epidermal Using reverse transcription polymerase chain reaction
growth factor (EGF) and other EGF receptor (EGFR) with primers specific to MR subtypes, radiolabeled ligand
agonists play key roles in promoting growth of many binding assays, and calcium mobilization studies, Frucht
human cancers, including CRC. As a result, biologicals et al. [13,14] reported that 60% of colon cancer cell lines they
that target EGFR have been approved by the Food and tested expressed M3R. Subsequently, Yang and Frucht [15]
Drug Administration for the treatment of EGFR-positive reported up to 8-fold increased M3R expression in 62% of
advanced CRC; this approach enhances survival by colon cancers compared to normal adjacent normal colon
several months. [4,5] However, the 5-year survival rate for epithelium.

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How to cite this article: Xie G, Raufman JP. Muscarinic receptor
signaling and colon cancer progression. J Cancer Metastasis Treat
DOI: 2016;2:195-200.
10.20517/2394-4722.2016.05
Received: 20-01-2016; Accepted: 03-06-2016.

©2016 Journal of Cancer Metastasis and Treatment ¦ Published by OAE Publishing Inc. 195