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, Andre Terzic, S. A. Waldman

Research output: Contribution to journalArticle

122 Citations (Scopus)

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 cellpermeant 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.

Original languageEnglish (US)
Pages (from-to)2695-2699
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number5
DOIs
StatePublished - Mar 4 2003

Fingerprint

Enterotoxins
Colonic Neoplasms
Diltiazem
Colorectal Neoplasms
Hot Temperature
Cyclic Nucleotide-Gated Cation Channels
Primary Prevention
Developed Countries
Population
Developing Countries
Neoplasms
Cell Proliferation
Bacteria
DNA
Incidence

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Pitari, G. M., Zingman, L. V., Hodgson, D. M., Alekseev, A. E., Kazerounian, S., Bienengraeber, M., ... Waldman, S. A. (2003). Bacterial enterotoxins are associated with resistance to colon cancer. Proceedings of the National Academy of Sciences of the United States of America, 100(5), 2695-2699. https://doi.org/10.1073/pnas.0434905100

Bacterial enterotoxins are associated with resistance to colon cancer. / Pitari, G. M.; Zingman, L. V.; Hodgson, D. M.; Alekseev, A. E.; Kazerounian, S.; Bienengraeber, M.; Hajnóczky, G.; Terzic, Andre; Waldman, S. A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 5, 04.03.2003, p. 2695-2699.

Research output: Contribution to journalArticle

Pitari, GM, Zingman, LV, Hodgson, DM, Alekseev, AE, Kazerounian, S, Bienengraeber, M, Hajnóczky, G, Terzic, A & Waldman, SA 2003, 'Bacterial enterotoxins are associated with resistance to colon cancer', Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 5, pp. 2695-2699. https://doi.org/10.1073/pnas.0434905100
Pitari, G. M. ; Zingman, L. V. ; Hodgson, D. M. ; Alekseev, A. E. ; Kazerounian, S. ; Bienengraeber, M. ; Hajnóczky, G. ; Terzic, Andre ; Waldman, S. A. / Bacterial enterotoxins are associated with resistance to colon cancer. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 5. pp. 2695-2699.
@article{9846488ce7a94af1a746fe37f414f625,
title = "Bacterial enterotoxins are associated with resistance to colon cancer",
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 cellpermeant 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.",
author = "Pitari, {G. M.} and Zingman, {L. V.} and Hodgson, {D. M.} and Alekseev, {A. E.} and S. Kazerounian and M. Bienengraeber and G. Hajn{\'o}czky and Andre Terzic and Waldman, {S. A.}",
year = "2003",
month = "3",
day = "4",
doi = "10.1073/pnas.0434905100",
language = "English (US)",
volume = "100",
pages = "2695--2699",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "5",

}

TY - JOUR

T1 - Bacterial enterotoxins are associated with resistance to colon cancer

AU - Pitari, G. M.

AU - Zingman, L. V.

AU - Hodgson, D. M.

AU - Alekseev, A. E.

AU - Kazerounian, S.

AU - Bienengraeber, M.

AU - Hajnóczky, G.

AU - Terzic, Andre

AU - Waldman, S. A.

PY - 2003/3/4

Y1 - 2003/3/4

N2 - 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 cellpermeant 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.

AB - 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 cellpermeant 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.

UR - http://www.scopus.com/inward/record.url?scp=0345701291&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0345701291&partnerID=8YFLogxK

U2 - 10.1073/pnas.0434905100

DO - 10.1073/pnas.0434905100

M3 - Article

C2 - 12594332

AN - SCOPUS:0345701291

VL - 100

SP - 2695

EP - 2699

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 5

ER -