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Carcinogenesis Advance Access published online on June 19, 2008
Carcinogenesis, doi:10.1093/carcin/bgn148
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Enterotoxin Preconditioning Restores Calcium-Sensing Receptor-Mediated Cytostasis in Colon Cancer Cells

Giovanni M.Pitari, Jieru E.Lin, Fawad J.Shah, Wilhelm J.Lubbe, David Zuzga, Peng Li, Stephanie Schulz and Scott A.Waldman

Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA

Corresponding Author: Giovanni M. Pitari, MD, PhD, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1100 Walnut St., MOB Suite 810, Philadelphia, PA 19107; Tel.: +(1) 215 955 5647; Fax: +(1) 215 955 7006; E-mail: Giovanni.Pitari{at}jefferson.edu

Guanylyl cyclase C (GCC), the receptor for diarrheagenic bacterial enterotoxins (STs), inhibits colorectal cancer cell proliferation by co-opting Ca2+ as the intracellular messenger. Similarly, extracellular Ca2+ (Ca2+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 Ca2+o. Here, preconditioning with ST, mediated by GCC signaling through cyclic nucleotide-gated channels, restored Ca2+o-dependent cytostasis, reflecting post-transcriptional regulation of Ca2+o-sensing receptors (CaRs). ST-induced GCC signaling deployed CaRs to the surface of human colon cancer cells, while elimination of GCC signaling in mice nearly abolished CaR expression in enterocytes. Moreover, ST-induced Ca2+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 Ca2+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 Ca2+ supplementation.

Key Words: Colorectal cancer • Guanylyl cyclase C • Bacterial enterotoxins • Calcium-sensing receptor

Received January 18, 2008; revised May 8, 2008; accepted June 9, 2008.


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