Spermine oxidation induced by Helicobacter pylori results in apoptosis and DNA damage: implications for gastric carcinogenesis.
Oxidative stress is linked to carcinogenesis due to its ability to damage DNA. The human gastric pathogen Helicobacter pylori exerts much of its pathogenicity by inducing apoptosis and DNA damage in host gastric epithelial cells. Polyamines are abundant in epithelial cells, and when oxidized by the inducible spermine oxidase SMO(PAOh1) H(2)O(2) is generated. Here, we report that H. pylori up-regulates mRNA expression, promoter activity, and enzyme activity of SMO(PAOh1) in human gastric epithelial cells, resulting in DNA damage and apoptosis. H. pylori-induced H(2)O(2) generation and apoptosis in these cells was equally attenuated by an inhibitor of SMO(PAOh1), by catalase, and by transient transfection with small interfering RNA targeting SMO(PAOh1). Conversely, SMO(PAOh1) overexpression induced apoptosis to the same levels as caused by H. pylori. Importantly, in H. pylori-infected tissues, there was increased expression of SMO(PAOh1) in both human and mouse gastritis. Laser capture microdissection of human gastric epithelial cells demonstrated expression of SMO(PAOh1) that was significantly attenuated by H. pylori eradication. These results identify a pathway for oxidative stress-induced epithelial cell apoptosis and DNA damage due to SMO(PAOh1) activation by H. pylori that may contribute to the pathogenesis of the infection and development of gastric cancer.
Xu
Hangxiu
H
Department of Medicine, Division of Gastroenterology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Chaturvedi
Rupesh
R
Cheng
Yulan
Y
Bussiere
Francoise I
FI
Asim
Mohammad
M
Yao
Micheal D
MD
Potosky
Darryn
D
Meltzer
Stephen J
SJ
Rhee
Juong G
JG
Kim
Sung S
SS
Moss
Steven F
SF
Hacker
Amy
A
Wang
Yanlin
Y
Casero
Robert A
RA
Wilson
Keith T
KT
D017209:Apoptosis / Q000502:physiology*; D004249:DNA Damage / Q000502:physiology*; D004790:Enzyme Induction; D005753:Gastric Mucosa / Q000201:enzymology / Q000378:metabolism* / Q000382:microbiology*; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D016481:Helicobacter Infections / Q000201:enzymology / Q000378:metabolism*; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013096:Spermine / Q000378:metabolism*; D013270:Stomach / Q000201:enzymology / Q000382:microbiology; D013274:Stomach Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology*; D000097667:Polyamine Oxidase
D006861:Hydrogen Peroxide; D000587:Oxidoreductases Acting on CH-NH Group Donors; D012333:RNA, Messenger; D013096:Spermine; D000097667:Polyamine Oxidase