Muscarinic receptor signaling and colon cancer progression

Abstract

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.

Keywords

Muscarinic receptor / colon cancer / epidermal growth factor receptors / bile acids / acetylcholine

References

[1] Torre LA,Siegel RL,Lortet-Tieulent J.Global cancer statistics, 2012..CA Cancer J Clin2015;65:87-108

[2] Siegel R,Jemal A.Colorectal cancer statistics, 2014..CA Cancer J Clin2014;64:104-17

[3] Siegel RL,Jemal A.Cancer statistics, 2015..CA Cancer J Clin2015;65:5-29

[4] Modjtahedi H.Epidermal growth factor receptor inhibitors in cancer treatment: advances, challenges and opportunities..Anticancer Drugs2009;20:851-5

[5] Overman MJ.EGFR-targeted therapies in colorectal cancer..Dis Colon Rectum2007;50:1259-70

[6] Ilyas M.Wnt signalling and the mechanistic basis of tumour development..J Pathol2005;205:130-44

[7] Wess J.Molecular biology of muscarinic acetylcholine receptors..Crit Rev Neurobiol1996;10:69-99

[8] Wess J.Muscarinic acetylcholine receptor knockout mice: novel phenotypes and clinical implications..Annu Rev Pharmacol Toxicol2004;44:423-50

[9] Shah N,Cheng K.Muscarinic receptors and ligands in cancer..Am J Physiol Cell Physiol2009;296:C221-32

[10] Spindel ER.Muscarinic receptor agonists and antagonists: effects on cancer..Handb Exp Pharmacol2012;208:451-68 PMCID:PMC3604886

[11] Spindel ER.Cholinergic targets in lung cancer..Curr Pharm Des2016;22:2152-9 PMCID:PMC4961355

[12] Kruse AC,Gautam D,Christopoulos A.Muscarinic acetylcholine receptors: novel opportunities for drug development..Nat Rev Drug Discov2014;13:549-60 PMCID:PMC5818261

[13] Frucht H,Park JA,Jensen RT.Characterization of functional receptors for gastrointestinal hormones on human colon cancer cells..Cancer Res1992;52:1114-22

[14] Frucht H,Dexter D,Xiao Y.Human colon cancer cell proliferation mediated by the M3 muscarinic cholinergic receptor..Clin Cancer Res1999;5:2532-9

[15] Yang WL.Cholinergic receptor up-regulates COX-2 expression and prostaglandin E(2) production in colon cancer cells..Carcinogenesis2000;21:1789-93

[16] Grando SA.Biological functions of keratinocyte cholinergic receptors..J Investig Dermatol Symp Proc1997;2:41-8

[17] Schlereth T,an Haack K,Kilbinger H,Wessler I.in vivo release of non-neuronal acetylcholine from the human skin as measured by dermal microdialysis: effect of botulinum toxin..Br J Pharmacol2006;147:183-7 PMCID:PMC1615863

[18] Song P,Jia Y,Blusztajn JK,Spindel ER.Acetylcholine is synthesized by and acts as an autocrine growth factor for small cell lung carcinoma..Cancer Res2003;63:214-21

[19] Tsuji S.Acetylcholine in neurons and paraneurons: a histochemical study..Arch Histol Cytol1989;52:75-83

[20] Keely SJ.Epithelial acetylcholine -- a new paradigm for cholinergic regulation of intestinal fluid and electrolyte transport..J Physiol2011;589:771-2 PMCID:PMC3060351

[21] Rosas-Ballina M,Ochani M,Levine YA,Tusche MW,Andersson U,Mak TW.Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit..Science2011;334:98-101 PMCID:PMC4548937

[22] Brandon EP,D'Amour KA,Dominguez B,Thode S,Thal LJ,Lee KF.Aberrant patterning of neuromuscular synapses in choline acetyltransferase-deficient mice..J Neurosci2003;23:539-49

[23] Klapproth H,Metzen J,Bittinger F,Höhle KD,Racké K.Non-neuronal acetylcholine, a signalling molecule synthezised by surface cells of rat and man..Naunyn Schmiedebergs Arch Pharmacol1997;355:515-23

[24] Cheng K,Xie G,Drachenberg C,Davis RJ,Raufman JP.Acetylcholine release by human colon cancer cells mediates autocrine stimulation of cell proliferation..Am J Physiol Gastrointest Liver Physiol2008;295:G591-7

[25] von Rosenvinge EC,Drachenberg CB,Evers DL,Raufman JP.Bedside to bench: role of muscarinic receptor activation in ultrarapid growth of colorectal cancer in a patient with pheochromocytoma..Mayo Clin Proc2013;88:1340-6 PMCID:PMC4076953

[26] Raufman JP,Bartoszko-Malik A.Lithocholyltaurine interacts with cholinergic receptors on dispersed chief cells from guinea pig stomach..Am J Physiol1998;274:G997-1004

[27] Raufman JP,Cheng K,Compadre L.Selective interaction of bile acids with muscarinic receptors: a case of molecular mimicry..Eur J Pharmacol2002;457:77-84

[28] Cheng K,Chen Y,Zimniak P.Lithocholylcholine, a bile acid/acetylcholine hybrid, is a muscarinic receptor antagonist..J Pharmacol Exp Ther2002;303:29-35

[29] Cheng K,Zimniak P,Xiao Y.Functional interaction of lithocholic acid conjugates with M3 muscarinic receptors on a human colon cancer cell line..Biochim Biophys Acta2002;1588:48-55

[30] Cheng K.Bile acid-induced proliferation of a human colon cancer cell line is mediated by transactivation of epidermal growth factor receptors..Biochem Pharmacol2005;70:1035-47

[31] Cheng K,Raufman JP.Transactivation of the epidermal growth factor receptor mediates cholinergic agonist-induced proliferation of H508 human colon cancer cells..Cancer Res2003;63:6744-50

[32] Raufman JP,Zimniak P.Deoxycholic acid conjugates are muscarinic cholinergic receptor antagonists..Pharmacology2002;65:215-21

[33] Cheng K,Raufman JP.Matrix metalloproteinase-7-catalyzed release of HB-EGF mediates deoxycholyltaurine-induced proliferation of a human colon cancer cell line..Biochem Pharmacol2007;73:1001-12 PMCID:PMC1852457

[34] Hamilton JP,Raufman JP,Griffin TL,Chatfield DA,Steinbach JH.Human cecal bile acids: concentration and spectrum..Am J Physiol Gastrointest Liver Physiol2007;293:G256-63

[35] Winawer S,Rex D,Burt R,Ganiats T,Woolf S,Kirk L,Simmang C.Colorectal cancer screening and surveillance: clinical guidelines and rationale-update based on new evidence..Gastroenterology2003;124:544-60

[36] Soler AP,Laughlin KV,Klurfeld DM.Increased tight junctional permeability is associated with the development of colon cancer..Carcinogenesis1999;20:1425-31

[37] Flynn C,Swank DL,Ilsley JN.Deoxycholic acid promotes the growth of colonic aberrant crypt foci..Mol Carcinog2007;46:60-70

[38] Dawson PA,Craddock AL,Tietjen M,Maeda N.Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice..J Biol Chem2003;278:33920-7

[39] Raufman JP,Rao A,Heath J,Hu S,Polli JE.Slc10a2-null mice uncover colon cancer-promoting actions of endogenous fecal bile acids..Carcinogenesis2015;36:1193-200 PMCID:PMC4612337

[40] Salomon DS,Ciardiello F.Epidermal growth factor-related peptides and their receptors in human malignancies..Crit Rev Oncol Hematol1995;19:183-232

[41] Ozğul C,Erdoğan D.Expression of epidermal growth factor receptor in normal colonic mucosa and in adenocarcinomas of the colon..Acta Physiol Hung1997;85:121-8

[42] Xie G,Shant J.Acetylcholine-induced activation of M3 muscarinic receptors stimulates robust matrix metalloproteinase gene expression in human colon cancer cells..Am J Physiol Gastrointest Liver Physiol2009;296:G755-63

[43] Raufman JP,Shah N,Shant J,Xie G,Cheng K.Genetic ablation of M3 muscarinic receptors attenuates murine colon epithelial cell proliferation and neoplasia..Cancer Res2008;68:3573-8 PMCID:PMC2577901

[44] Raufman JP,Xie G,Gao XM,Shah N,Heath J,Khurana S.Muscarinic receptor subtype-3 gene ablation and scopolamine butylbromide treatment attenuate small intestinal neoplasia in Apcmin/+ mice..Carcinogenesis2011;32:1396-402 PMCID:PMC3165126

[45] Cheng K,Khurana S,Drachenberg CB,Shah N.Divergent effects of muscarinic receptor subtype gene ablation on murine colon tumorigenesis reveals association of M3R and zinc finger protein 277 expression in colon neoplasia..Mol Cancer2014;13:77 PMCID:PMC4021221

[46] Peng Z,Drachenberg C,Xie G.Cholinergic muscarinic receptor activation augments murine intestinal epithelial cell proliferation and tumorigenesis..BMC Cancer2013;13:204 PMCID:PMC3640951

[47] Belo A,Chahdi A,Xie G,Raufman JP.Muscarinic receptor agonists stimulate human colon cancer cell migration and invasion..Am J Physiol Gastrointest Liver Physiol2011;300:G749-60

[48] Raufman JP,Saxena N,Belo A,Xie G.Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells..Biochem Biophys Res Commun2011;415:319-24 PMCID:PMC3221914

[49] Philip AK.Colon targeted drug delivery systems: a review on primary and novel approaches..Oman Med J2010;25:79-87