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Proc Natl Acad Sci U S A. 2019 Mar 12;116(11):5077-5085. doi: 10.1073/pnas.1814497116. Epub 2019 Feb 25.

α-Difluoromethylornithine reduces gastric carcinogenesis by causing mutations in Helicobacter pylori cagY.

Author information

1
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
2
Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN 37232.
3
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232.
4
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232.
5
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; keith.wilson@vumc.org.
6
Medical Service, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212.
7
Research Service, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212.

Abstract

Infection by Helicobacter pylori is the primary cause of gastric adenocarcinoma. The most potent H. pylori virulence factor is cytotoxin-associated gene A (CagA), which is translocated by a type 4 secretion system (T4SS) into gastric epithelial cells and activates oncogenic signaling pathways. The gene cagY encodes for a key component of the T4SS and can undergo gene rearrangements. We have shown that the cancer chemopreventive agent α-difluoromethylornithine (DFMO), known to inhibit the enzyme ornithine decarboxylase, reduces H. pylori-mediated gastric cancer incidence in Mongolian gerbils. In the present study, we questioned whether DFMO might directly affect H. pylori pathogenicity. We show that H. pylori output strains isolated from gerbils treated with DFMO exhibit reduced ability to translocate CagA in gastric epithelial cells. Further, we frequently detected genomic modifications in the middle repeat region of the cagY gene of output strains from DFMO-treated animals, which were associated with alterations in the CagY protein. Gerbils did not develop carcinoma when infected with a DFMO output strain containing rearranged cagY or the parental strain in which the wild-type cagY was replaced by cagY with DFMO-induced rearrangements. Lastly, we demonstrate that in vitro treatment of H. pylori by DFMO induces oxidative DNA damage, expression of the DNA repair enzyme MutS2, and mutations in cagY, demonstrating that DFMO directly affects genomic stability. Deletion of mutS2 abrogated the ability of DFMO to induce cagY rearrangements directly. In conclusion, DFMO-induced oxidative stress in H. pylori leads to genomic alterations and attenuates virulence.

KEYWORDS:

Helicobacter pylori; chemoprevention; difluoromethylornithine; gastric cancer; polyamines

PMID:
30804204
PMCID:
PMC6421409
[Available on 2019-08-25]
DOI:
10.1073/pnas.1814497116
[Indexed for MEDLINE]

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