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Mitogenic CA2+ entry through ICRAC channels reciprocally regulates the tumor suppressor guanylyl cyclase C (GCC)
Author(s) -
Frick G. S.,
Kazerounian S.,
Shah F. J.,
Madesh M.,
RuizStewart I.,
Schulz S.,
Hajanóczky G.,
Waldman S. A.,
Pitari G. M.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.180
Subject(s) - intracellular , extracellular , cell growth , chemistry , soluble guanylyl cyclase , microbiology and biotechnology , forskolin , signal transduction , thapsigargin , cancer research , receptor , biochemistry , biology , guanylate cyclase
Guanylyl cyclase C (GCC) through cyclic GMP (cGMP) inhibits colorectal cancer cell proliferation, serving as a tumor suppressor in intestine. Conversely, Ca 2+ entry through calcium release‐activated calcium (I crac ) channels promotes colorectal cancer growth. The present study explored the functional relationship between mitogenic signaling by Ca 2+ entry through I crac channels and antiproliferative signaling by GCC in T84 human colon carcinoma cells. The E. coli heat‐stable enterotoxin ST, a specific GCC ligand, induced intracellular accumulation of cGMP, Ca 2+ entry through CNG channels and inhibition of human colorectal cancer cell proliferation. In contrast, influx of extracellular Ca 2+ through I crac channels, induced by thapsigargin, UTP or carbachol, inhibited GCC‐dependent cGMP accumulation. Chelating intracellular Ca 2+ , removing extracellular Ca 2+ , or specifically blocking I crac channels with the antagonist 2‐APB reversed this inhibition. Moreover, 2‐APB blocked Ca 2+ ‐dependent cell proliferation and amplified the anti‐proliferative effects of ST. These data suggest that an imbalance of pro‐ and anti‐mitogenic signals mediated by Ca 2+ may contribute to mechanisms underlying colorectal carcinogenesis. In addition, they suggest that the combination of GCC agonists and I crac channel inhibitors represents a novel paradigm for cGMP‐directed therapy for colorectal tumors. Clinical Pharmacology & Therapeutics (2004) 75 , P48–P48; doi: 10.1016/j.clpt.2003.11.180