A crosstalk between muscarinic and CRF2 receptors regulates cellular adhesion properties of human colon cancer cells

In this study, we investigated the mechanisms through which stress and ACh modulate epithelial cell adhesive properties. We show that ACh-induced activation of mAChR in HT-29 cells results in cell dissociation together with changes in cell-matrix contacts, which correlates with the acquisition of invasive potential consistent with a matrix metalloproteinase (MMP) mode of invasion. These processes result from mAChR subsequent stimulation of the cascade of src/Erk and FAK activation. ACh-induced secretion of laminin 332 leads to α3β1 integrin activation and RhoA-dependent reorganization of the actin cytoskeleton. We show that ACh-mediated effects on cell adhesion are blocked by astressin 2b, a CRF2 antagonist, suggesting that ACh action depends partly on CRF2 signaling. This is reinforced by the fact that ACh-mediated activation of mAChR stimulates both the synthesis and the release of CRF2 ligands in HT-29 cells (effects blocked by atropine). In summary, our data provides evidence for a novel intracellular circuit involving mAChR acting on CRF2-signaling that could mediate colonic mucosal barrier dysfunction and exacerbate mucosal inflammation.
Source: Biochimica et Biophysica Acta (BBA) Molecular Cell Research - Category: Molecular Biology Source Type: research