Enterotoxin preconditioning restores calcium-sensing receptor-mediated cytostasis in colon cancer cells.
Publication/Presentation Date
8-1-2008
Abstract
Guanylyl cyclase C (GCC), the receptor for diarrheagenic bacterial heat-stable enterotoxins (STs), inhibits colorectal cancer cell proliferation by co-opting Ca(2+) as the intracellular messenger. Similarly, extracellular Ca(2+) (Ca(2+)(o)) opposes proliferation and induces terminal differentiation in intestinal epithelial cells. In that context, human colon cancer cells develop a phenotype characterized by insensitivity to cytostasis imposed by Ca(2+)(o). Here, preconditioning with ST, mediated by GCC signaling through cyclic nucleotide-gated channels, restored Ca(2+)(o)-dependent cytostasis, reflecting posttranscriptional regulation of calcium-sensing receptors (CaRs). ST-induced GCC signaling deployed CaRs to the surface of human colon cancer cells, whereas elimination of GCC signaling in mice nearly abolished CaR expression in enterocytes. Moreover, ST-induced Ca(2+)(o)-dependent cytostasis was abrogated by CaR-specific antisense oligonucleotides. Importantly, following ST preconditioning, newly expressed CaRs at the cell surface represented tumor cell receptor targets for antiproliferative signaling by CaR agonists. Since expression of the endogenous paracrine hormones for GCC is uniformly lost early in carcinogenesis, these observations offer a mechanistic explanation for the Ca(2+)(o)-resistant phenotype of colon cancer cells. Restoration of antitumorigenic CaR signaling by GCC ligand replacement therapy represents a previously unrecognized paradigm for the prevention and treatment of human colorectal cancer employing dietary Ca(2+) supplementation.
Volume
29
Issue
8
First Page
1601
Last Page
1607
ISSN
1460-2180
Published In/Presented At
Pitari, G. M., Lin, J. E., Shah, F. J., Lubbe, W. J., Zuzga, D. S., Li, P., Schulz, S., & Waldman, S. A. (2008). Enterotoxin preconditioning restores calcium-sensing receptor-mediated cytostasis in colon cancer cells. Carcinogenesis, 29(8), 1601–1607. https://doi.org/10.1093/carcin/bgn148
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
18566015
Department(s)
Administration and Leadership
Document Type
Article