title: 4-hydroxy-2-nonenal mediates genotoxicity and bystander effects caused by Enterococcus faecalis-infected macrophages.
abstract: OBJECTIVE
  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.
authors: The Muchmore Laboratories for Infectious Diseases Research, Research Service, Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73104, USA.
authors: Xingmin
authors: X
authors: Wang
authors: Yonghong
authors: Y
authors: Yang
authors: Danny R
authors: DR
authors: Moore
authors: Susan L
authors: SL
authors: Nimmo
authors: Stanley A
authors: SA
authors: Lightfoot
authors: Mark M
authors: MM
authors: Huycke
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D019898:Autocrine Communication; D001706:Biopsy; D024201:Bystander Effect; D018920:Coculture Techniques; D003106:Colon / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D004249:DNA Damage; D004195:Disease Models, Animal; D013293:Enterococcus faecalis / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D059565:G2 Phase Cell Cycle Checkpoints; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D016908:Gram-Positive Bacterial Infections / Q000235:genetics / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D045325:HCT116 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D008941:Spindle Apparatus / Q000378:metabolism / Q000473:pathology; D050777:Stathmin / Q000378:metabolism; D057891:Tetraploidy; D013997:Time Factors; D014162:Transfection
chemical_list: D000447:Aldehydes; C468783:H2AX protein, human; D006657:Histones; C556062:IL10 protein, mouse; C493995:STMN1 protein, human; D050777:Stathmin; C493994:Stmn1 protein, mouse; C475961:gamma-H2AX protein, mouse; D016753:Interleukin-10; D005982:Glutathione Transferase; C412602:glutathione S-transferase Mu 2; C027576:4-hydroxy-2-nonenal