Journal Article

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

in Carcinogenesis

Volume 29, issue 8, pages 1601-1607
Published in print August 2008 | ISSN: 0143-3334
Published online June 2008 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgn148
Enterotoxin preconditioning restores calcium-sensing receptor-mediated cytostasis in colon cancer cells

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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.

Journal Article.  5078 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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