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Enterococcus faecalis Induces Aneuploidy and Tetraploidy in Colonic Epithelial Cells through a Bystander Effect

¹ The Muchmore Laboratories for Infectious Diseases Research, Research Service, Department of Veterans Affairs Medical Center, and Departments of ² Medicine and ³ Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Requests for reprints: Mark M. Huycke, Medical Service (111), Department of Veterans Affairs Medical Center, 921 NE 13th Street, Oklahoma City, OK 73104. Phone: 405-456-3250; Fax: 405-456-5948; E-mail: mark-huycke{at}ouhsc.edu.

Key Words: aneuploidy • chromosomal instability • Enterococcus faecalis • DNA damage • G₂-phase cell cycle arrest

Intestinal commensals are potential important contributors to the etiology of sporadic colorectal cancer, but mechanisms by which bacteria can initiate tumors remain uncertain. Herein, we describe mechanisms that link Enterococcus faecalis, a bacterium known to produce extracellular superoxide, to the acute induction of chromosomal instability. Immortalized human and nontransformed murine colonic epithelial cells, along with a mouse colonic ligation model, were used to assess the effect of E. faecalis on genomic DNA stability and damage. We found that this human intestinal commensal generated aneuploidy, tetraploidy, and H2AX foci in HCT116, RKO, and YAMC cells. In addition, direct exposure of E. faecalis to these cells induced a G₂ cell cycle arrest. Similar observations were noted by exposing cells to E. faecalis–infected macrophages in a dual-chamber coculture system for detecting bystander effects. Manganese superoxide dismutase, catalase, and tocopherols attenuated, and caffeine and inhibitors of glutathione synthase exacerbated, the aneugenic effects and linked the redox-active phenotype of this intestinal commensal to potentially transforming events. These findings provide novel insights into mechanisms by which E. faecalis and intestinal commensals can contribute to cellular transformation and tumorigenesis. [Cancer Res 2008;68(23):9909–17]