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

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.

• Authors: Johanna C Sierra, Giovanni Suarez, M Blanca Piazuelo, Paula B Luis, Dara R Baker, Judith Romero-Gallo, Daniel P Barry, Claus Schneider, Douglas R Morgan, Richard M Peek Jr, Alain P Gobert, Keith T Wilson
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 11 Pg. 5077-5085 (03 12 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 30804204 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Bacterial Proteins
• RNA, Messenger
• Eflornithine

Topics

• Animals
• Bacterial Proteins (genetics)
• Carcinogenesis (genetics, pathology)
• DNA Damage
• Eflornithine (pharmacology)
• Gene Deletion
• Gene Rearrangement
• Gerbillinae
• Helicobacter pylori (drug effects, genetics, pathogenicity)
• Male
• Mutation (genetics)
• Oxidative Stress (drug effects)
• RNA, Messenger (genetics, metabolism)
• Stomach Neoplasms (microbiology, pathology)
• Virulence