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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 3, 2005; DOI: 10.1124/jpet.105.089052

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Received for publication May 4, 2005.
Revised May 28, 2005.
Accepted for publication June 1, 2005.

Proliferative Signaling by Store-Operated Calcium Channels Opposes Colon Cancer Cell Cytostasis Induced By Bacterial Enterotoxins

Shiva Kazerounian 1, Giovanni M Pitari 1, Fawad J Shah 1, Glen S Frick 1, Muniswamy Madesh 1, Inez Ruiz-Stewart 1, Stephanie Schulz 1, Gyorgy Hajnoczky 1, Scott A Waldman 1*

1 Thomas Jefferson University

* Address correspondence to: E-mail: scott.waldman{at}jefferson.edu

Abstract

Guanylyl cyclase C and accumulation of cGMP induced by bacterial heat-stable enterotoxins (STs) promotes colon cancer cell cytostasis, serving as a tumor suppressor in intestine. Conversely, capacitative calcium entry through store-operated calcium channels (SOCs) is a key signaling mechanism promoting colon cancer cell proliferation. The present study revealed that proliferative signaling by capacitative calcium entry through SOCs opposes, and is reciprocally coupled to, cytostasis mediated by guanylyl cyclase C in T84 human colon carcinoma cells. Elimination of capacitative calcium entry employing 2-APB, a selective inhibitor of SOCs, potentiated cytostasis induced by ST. Opposition of ST-induced cytostasis by capacitative calcium entry reflects reciprocal inhibition of guanylyl cyclase C signaling. Calcium entry through SOCs induced by the calcium-ATPase inhibitor thapsigargin or the receptor agonists UTP or carbachol, inhibited guanylyl cyclase C-dependent cGMP accumulation. This effect was mimicked by the calcium ionophore ionomycin and blocked by 2-APB and intracellular BAPTA-AM, a chelator of calcium. Moreover, regulation by capacitative calcium entry reflected ligand-dependent sensitization of guanylyl cyclase C to inhibition by that cation. While basal catalytic activity was refractory, ST-stimulated guanylyl cyclase C was inhibited by calcium, which antagonized binding of magnesium to allosteric sites required for receptor-effector coupling. These observations demonstrate that reciprocal regulation of guanylyl cyclase C signaling by capacitative calcium entry through SOCs represents one limb of a coordinated mechanism balancing colon cancer cell proliferation and cytostasis. They suggest that combining guanylyl cyclase C agonists and SOC inhibitors offers a novel paradigm for cGMP-directed therapy and prevention for colorectal tumors.


Key words: Calcium, Colon cancer, Cyclic GMP, Guanylyl cyclase C, Proliferation, Store-operated calcium channels


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