Bacterial enterotoxins are associated with resistance to colon cancer
- G. M. Pitari*,†,
- L. V. Zingman‡,
- D. M. Hodgson‡,
- A. E. Alekseev‡,
- S. Kazerounian*,
- M. Bienengraeber‡,
- G. Hajnóczky§,
- A. Terzic‡, and
- S. A. Waldman*
- *Division of Clinical Pharmacology, Departments of Medicine, Biochemistry, and Molecular Pharmacology, and §Departments of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107; and ‡Departments of Medicine, Molecular Pharmacology, and Experimental Therapeutics, Division of Cardiovascular Diseases, Mayo Clinic, Mayo Foundation, Rochester, MN 55905
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Edited by Joseph A. Beavo, University of Washington School of Medicine, Seattle, WA, and approved December 27, 2002 (received for review August 14, 2002)
Abstract
One half million patients suffer from colorectal cancer in industrialized nations, yet this disease exhibits a low incidence in under-developed countries. This geographic imbalance suggests an environmental contribution to the resistance of endemic populations to intestinal neoplasia. A common epidemiological characteristic of these colon cancer-spared regions is the prevalence of enterotoxigenic bacteria associated with diarrheal disease. Here, a bacterial heat-stable enterotoxin was demonstrated to suppress colon cancer cell proliferation by a guanylyl cyclase C-mediated signaling cascade. The heat-stable enterotoxin suppressed proliferation by increasing intracellular cGMP, an effect mimicked by the cell-permeant analog 8-br-cGMP. The antiproliferative effects of the enterotoxin and 8-br-cGMP were reversed by L-cis-diltiazem, a cyclic nucleotide-gated channel inhibitor, as well as by removal of extracellular Ca2+, or chelation of intracellular Ca2+. In fact, both the enterotoxin and 8-br-cGMP induced an L-cis-diltiazem-sensitive conductance, promoting Ca2+ influx and inhibition of DNA synthesis in colon cancer cells. Induction of this previously unrecognized antiproliferative signaling pathway by bacterial enterotoxin could contribute to the resistance of endemic populations to intestinal neoplasia, and offers a paradigm for targeted prevention and therapy of primary and metastatic colorectal cancer.
Footnotes
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↵ † To whom correspondence should be addressed at: Division of Clinical Pharmacology, Thomas Jefferson University, 1100 Walnut Street, MOB 811, Philadelphia, PA 19107. E-mail: gmpitari{at}yahoo.com.
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This paper was submitted directly (Track II) to the PNAS office.
- Abbreviations:
- ETEC,
- enterotoxigenic Escherichia coli;
- STs,
- heat-stable enterotoxins;
- GC-C,
- guanylyl cyclase C;
- PKG,
- cyclic GMP-dependent protein kinase;
- CNG channels,
- cyclic nucleotide-gated channels;
- L-DLT,
- L-cis-diltiazem;
- [cGMP]i,
- intracellular cGMP
- Copyright © 2003, The National Academy of Sciences
