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; S A Waldman

doi:10.1073/pnas.0434905100

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Bacterial enterotoxins are associated with resistance to colon cancer

Journal article

Open access

Peer reviewed

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

Proceedings of the National Academy of Sciences - PNAS, Vol.100(5), pp.2695-2699

03/04/2003

DOI: 10.1073/pnas.0434905100

PMCID: PMC151403

PMID: 12594332

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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 Ca(2+), or chelation of intracellular Ca(2+). In fact, both the enterotoxin and 8-br-cGMP induced an L-cis-diltiazem-sensitive conductance, promoting Ca(2+) 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.

Calcium - metabolism

Colonic Neoplasms - prevention & control

Humans

Colonic Neoplasms - metabolism

Dose-Response Relationship, Drug

Peptides - metabolism

Gastrointestinal Hormones - metabolism

Receptors, Peptide

Cell Differentiation

Tumor Cells, Cultured

Colonic Neoplasms - therapy

Membrane Potentials - drug effects

Signal Transduction

Receptors, Cell Surface - metabolism

DNA - metabolism

Receptors, Enterotoxin

Immunity, Innate

Cell Division - drug effects

Receptors, Guanylate Cyclase-Coupled

Natriuretic Peptides

Patch-Clamp Techniques

Escherichia coli Proteins

Guanylate Cyclase

Bacterial Toxins - pharmacology

Colonic Neoplasms - pathology

Ligands

Enterotoxins - pharmacology

Details

Title: Subtitle: Bacterial enterotoxins are associated with resistance to colon cancer
Creators: G M Pitari - Division of Clinical Pharmacology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA. gmpitari@yahoo.com
L V Zingman
D M Hodgson
A E Alekseev
S Kazerounian
M Bienengraeber
G Hajnóczky
A Terzic
S A Waldman
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.100(5), pp.2695-2699
DOI: 10.1073/pnas.0434905100
PMID: 12594332
PMCID: PMC151403
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Grant note: HL59214 / NHLBI NIH HHS CA7966 / NCI NIH HHS T32 HL007111 / NHLBI NIH HHS HL07111 / NHLBI NIH HHS R01 HL064822 / NHLBI NIH HHS CA7512 / NCI NIH HHS HL64822 / NHLBI NIH HHS HL65921 / NHLBI NIH HHS
Language: English
Date published: 03/04/2003
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984094364602771

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