Enterotoxin preconditioning restores calcium-sensing receptor-mediated cytostasis in colon cancer cells.
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.
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1100 Walnut Street, MOB Suite 810, Philadelphia, PA 19107, USA. giovanni.pitari@jefferson.edu
Giovanni M
GM
Pitari
Jieru E
JE
Lin
Fawad J
FJ
Shah
Wilhelm J
WJ
Lubbe
David S
DS
Zuzga
Peng
P
Li
Stephanie
S
Schulz
Scott A
SA
Waldman
D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000473:pathology; D004768:Enterotoxins / Q000494:pharmacology*; D006801:Humans; D019194:Ischemic Preconditioning; D009336:Necrosis; D044169:Receptors, Calcium-Sensing / Q000187:drug effects / Q000502:physiology*
D004768:Enterotoxins; D044169:Receptors, Calcium-Sensing