Bacterial enterotoxins are associated with resistance to colon cancer. Proc Natl Acad Sci U S A 2003 Mar 04;100(5):2695-9
Date
02/21/2003Pubmed ID
12594332Pubmed Central ID
PMC151403DOI
10.1073/pnas.0434905100Scopus ID
2-s2.0-0345701291 (requires institutional sign-in at Scopus site) 134 CitationsAbstract
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.
Author List
Pitari GM, Zingman LV, Hodgson DM, Alekseev AE, Kazerounian S, Bienengraeber M, Hajnóczky G, Terzic A, Waldman SAMESH terms used to index this publication - Major topics in bold
Bacterial ToxinsCalcium
Cell Differentiation
Cell Division
Colonic Neoplasms
DNA
Dose-Response Relationship, Drug
Enterotoxins
Escherichia coli Proteins
Gastrointestinal Hormones
Guanylate Cyclase
Humans
Immunity, Innate
Ligands
Membrane Potentials
Natriuretic Peptides
Patch-Clamp Techniques
Peptides
Receptors, Cell Surface
Receptors, Enterotoxin
Receptors, Guanylate Cyclase-Coupled
Receptors, Peptide
Signal Transduction
Tumor Cells, Cultured
