BACKGROUND & AIMS: Enterococcus faecalis is a human intestinal commensal that produces extracellular superoxide and promotes chromosome instability via macrophage-induced bystander effects. We investigated the ability of 4-hydroxy-2-nonenal (4-HNE), a diffusible breakdown product of ω-6 polyunsaturated fatty acids, to mediate these effects. METHODS: 4-HNE was purified from E faecalis-infected macrophages; its genotoxicity was assessed in human colon cancer (HCT116) and primary murine colon epithelial (YAMC) cell lines. RESULTS: 4-HNE induced G(2)-M cell cycle arrest, led to formation γH2AX foci, and disrupted the mitotic spindle in both cell lines. Binucleate tetraploid cells that formed after incubation with 4-HNE were associated with the activation of stathmin and microtubule catastrophe. Silencing glutathione S-transferase α4, a scavenger of 4-HNE, increased the susceptibility of epithelial cells to 4-HNE-induced genotoxicity. Interleukin-10 knockout mice colonized with superoxide-producing E faecalis developed inflammation and colorectal cancer, whereas colonization with a superoxide-deficient strain resulted in inflammation but not cancer. 4-HNE-protein adducts were found in the lamina propria and macrophages in areas of colorectal inflammation. CONCLUSIONS: 4-HNE can act as an autochthonous mitotic spindle poison in normal colonic epithelial and colon cancer cells. This finding links the macrophage-induced bystander effects to colorectal carcinogenesis. Copyright Â
BACKGROUND & AIMS:Enterococcus faecalis is a human intestinal commensal that produces extracellular superoxide and promotes chromosome instability via macrophage-induced bystander effects. We investigated the ability of 4-hydroxy-2-nonenal (4-HNE), a diffusible breakdown product of ω-6 polyunsaturated fatty acids, to mediate these effects. METHODS:4-HNE was purified from E faecalis-infected macrophages; its genotoxicity was assessed in humancolon cancer (HCT116) and primary murine colon epithelial (YAMC) cell lines. RESULTS:4-HNE induced G(2)-M cell cycle arrest, led to formation γH2AX foci, and disrupted the mitotic spindle in both cell lines. Binucleate tetraploid cells that formed after incubation with 4-HNE were associated with the activation of stathmin and microtubule catastrophe. Silencing glutathione S-transferase α4, a scavenger of 4-HNE, increased the susceptibility of epithelial cells to 4-HNE-induced genotoxicity. Interleukin-10 knockout mice colonized with superoxide-producing E faecalis developed inflammation and colorectal cancer, whereas colonization with a superoxide-deficient strain resulted in inflammation but not cancer. 4-HNE-protein adducts were found in the lamina propria and macrophages in areas of colorectal inflammation. CONCLUSIONS:4-HNE can act as an autochthonous mitotic spindle poison in normal colonic epithelial and colon cancer cells. This finding links the macrophage-induced bystander effects to colorectal carcinogenesis. Copyright Â
Authors: W Liu; M Kato; M Itoigawa; H Murakami; M Yajima; J Wu; N Ishikawa; I Nakashima Journal: J Cell Biochem Date: 2001 Aug 1-9 Impact factor: 4.429
Authors: Mark R Engle; Sharda P Singh; Piotr J Czernik; Dana Gaddy; Donna C Montague; Jeffrey D Ceci; Yusong Yang; Sanjay Awasthi; Yogesh C Awasthi; Piotr Zimniak Journal: Toxicol Appl Pharmacol Date: 2004-02-01 Impact factor: 4.219
Authors: Fong-Fong Chu; R Steven Esworthy; Peiguo G Chu; Jeffrey A Longmate; Mark M Huycke; Sharon Wilczynski; James H Doroshow Journal: Cancer Res Date: 2004-02-01 Impact factor: 12.701
Authors: Kenneth J Ritchie; Shaun Walsh; Owen J Sansom; Colin J Henderson; C Roland Wolf Journal: Proc Natl Acad Sci U S A Date: 2009-11-13 Impact factor: 11.205
Authors: Ulla G Knaus; Rosanne Hertzberger; Gratiela G Pircalabioru; S Parsa M Yousefi; Filipe Branco Dos Santos Journal: Gut Microbes Date: 2017-01-12