title: Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis.
abstract: It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation, although the direct molecular events linking inflammation and carcinogenesis are poorly defined. In the context of gastrointestinal disease, the bacterium enterotoxigenic Bacteroides fragilis (ETBF) is a significant source of chronic inflammation and has been implicated as a risk factor for colorectal cancer. Spermine oxidase (SMO) is a polyamine catabolic enzyme that is highly inducible by inflammatory stimuli resulting in increased reactive oxygen species (ROS) and DNA damage. We now demonstrate that purified B. fragilis toxin (BFT) up-regulates SMO in HT29/c1 and T84 colonic epithelial cells, resulting in SMO-dependent generation of ROS and induction of γ-H2A.x, a marker of DNA damage. Further, ETBF-induced colitis in C57BL/6 mice is associated with increased SMO expression and treatment of mice with an inhibitor of polyamine catabolism, N(1),N(4)-bis(2,3-butandienyl)-1,4-butanediamine (MDL 72527), significantly reduces ETBF-induced chronic inflammation and proliferation. Most importantly, in the multiple intestinal neoplasia (Min) mouse model, treatment with MDL 72527 reduces ETBF-induced colon tumorigenesis by 69% (P < 0.001). The results of these studies indicate that SMO is a source of bacteria-induced ROS directly associated with tumorigenesis and could serve as a unique target for chemoprevention.
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Goodwin
authors.forename: Christina E
authors.initials: CE
authors.lastname: Destefano Shields
authors.forename: Shaoguang
authors.initials: S
authors.lastname: Wu
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: XinQun
authors.initials: X
authors.lastname: Wu
authors.forename: Tracy R
authors.initials: TR
authors.lastname: Murray-Stewart
authors.forename: Amy
authors.initials: A
authors.lastname: Hacker-Prietz
authors.forename: Shervin
authors.initials: S
authors.lastname: Rabizadeh
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Woster
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Sears
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity; D001441:Bacteroides fragilis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000473:pathology; D003110:Colonic Neoplasms / Q000150:complications / Q000382:microbiology* / Q000473:pathology; D004249:DNA Damage; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000096:biosynthesis / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism*; D011230:Precancerous Conditions / Q000382:microbiology* / Q000473:pathology; D011700:Putrescine / Q000031:analogs & derivatives / Q000494:pharmacology; D011994:Recombinant Proteins / Q000633:toxicity; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D001427:Bacterial Toxins; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D011700:Putrescine; D011994:Recombinant Proteins; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase; C044445:MDL 72527; C501650:N(1)-acetylpolyamine oxidase, human