Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells.

Abstract

Mammalian matrix metalloproteinases (MMPs) which degrade extracellular matrix facilitate colon cancer cell invasion into the bloodstream and extra-colonic tissues; in particular, MMP1 expression correlates strongly with advanced colon cancer stage, hematogenous metastasis and poor prognosis. Likewise, muscarinic receptor signaling plays an important role in colon cancer; muscarinic receptors are over-expressed in colon cancer compared to normal colon epithelial cells. Muscarinic receptor activation stimulates proliferation, migration and invasion of human colon cancer cells. In mouse intestinal neoplasia models genetic ablation of muscarinic receptors attenuates carcinogenesis. In the present work, we sought to link these observations by showing that MMP1 expression and activation plays a mechanistic role in muscarinic receptor agonist-induced colon cancer cell invasion. We show that acetylcholine, which robustly increases MMP1 expression, stimulates invasion of HT29 and H508 human colon cancer cells into human umbilical vein endothelial cell monolayers - this was abolished by pre-incubation with atropine, a non-selective muscarinic receptor inhibitor, and by pre-incubation with anti-MMP1 neutralizing antibody. Similar results were obtained using a Matrigel chamber assay and deoxycholyltaurine (DCT), an amidated dihydroxy bile acid associated with colon neoplasia in animal models and humans, and previously shown to interact functionally with muscarinic receptors. DCT treatment of human colon cancer cells resulted in time-dependent, 10-fold increased MMP1 expression, and DCT-induced cell invasion was also blocked by pre-treatment with anti-MMP1 antibody. This study contributes to understanding mechanisms underlying muscarinic receptor agonist-induced promotion of colon cancer and, more importantly, indicates that blocking MMP1 expression and activation has therapeutic promise to stop or retard colon cancer invasion and dissemination.

• Authors: Jean-Pierre Raufman, Kunrong Cheng, Neeraj Saxena, Ahmed Chahdi, Angelica Belo, Sandeep Khurana, Guofeng Xie
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 415 Issue 2 Pg. 319-24 (Nov 18 2011) ISSN: 1090-2104 [Electronic] United States
• PMID: 22027145 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Muscarinic Agonists
• Receptors, Muscarinic
• Taurodeoxycholic Acid
• MMP1 protein, human
• Matrix Metalloproteinase 1
• Acetylcholine

Topics

• Acetylcholine (metabolism, pharmacology)
• Cell Movement (drug effects)
• Colonic Neoplasms (enzymology, pathology)
• HT29 Cells
• Humans
• Matrix Metalloproteinase 1 (genetics, metabolism)
• Muscarinic Agonists (pharmacology)
• Neoplasm Invasiveness
• Receptors, Muscarinic (metabolism)
• Taurodeoxycholic Acid (pharmacology)