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Carcinogenesis Advance Access originally published online on June 19, 2008
Carcinogenesis 2008 29(8):1601-1607; 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 S. Zuzga, Peng Li, Stephanie Schulz and Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1100 Walnut Street, MOB Suite 810, Philadelphia, PA 19107, USA

* To whom correspondence should be addressed. Tel: +1 215 955 5647; Fax: +1 215 955 7006; Email: giovanni.pitari{at}jefferson.edu

Guanylyl cyclase C (GCC), the receptor for diarrheagenic bacterial heat-stable 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 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 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.

Abbreviations: APC, adenomatous polyposis coli; Ca2+o, extracellular Ca2+; CaR, calcium-sensing receptor; CNG, cyclic nucleotide-gated; GCC, guanylyl cyclase C; ST, heat-stable enterotoxin

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


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