Bacteria-Induced Intestinal Cancer in Mice with DisruptedGpx1andGpx2Genes

Chu, Fong Fong; Esworthy, R. Steven; Chu, Peiguo; Longmate, Jeffrey; Huycke, Mark M.; Wilczynski, Sharon P.; Doroshow, James H.

doi:10.1158/0008-5472.can-03-2272

Cited by 275 publications

(222 citation statements)

References 61 publications

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“…The importance of bacterially-induced ROS in inflammation-associated carcinogenesis was demonstrated in mice lacking the H 2 O 2 detoxification enzymes gpx-1 and gpx-2. These animals have a normal phenotype when raised in germ-free conditions, but if colonized with conventional flora, they develop intestinal tumors (18). Although inflammation-associated ROS has been implicated as one of the sources for the mutagens necessary to produce the genetic changes required for the carcinogenic process, the sources of the ROS have not been clearly identified.…”

Section: Resultsmentioning

confidence: 99%

“…Enteric bacteria have been shown to induce ROS production (17), and mice lacking the Gpx-1 and Gpx-2 enzymes that protect against these free radicals are succeptible to microflora-dependent intestinal inflammation and tumorigenesis (18). Recent reports suggest that a potential source of this inflammation-associated ROS production is the polyamine catabolic enzyme spermine oxidase (SMO), which generates H 2 O 2 as a byproduct of the back conversion of spermine to spermidine (19,20).…”

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confidence: 99%

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Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Goodwin¹,

Shields²,

Wu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

501

353

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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) upregulates 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.inflammatory bowel diseases | adenomatous polyposis coli I t is estimated that chronic inflammation associated with microbial infection directly contributes to the etiology of about 20% of epithelial cancers. The chronic inflammatory microenvironment is characterized by immune dysregulation and elevated levels of reactive oxygen species [ROS; including superoxide, hydrogen peroxide (H 2 O 2 ), and singlet oxygen]. These features result in activation of stress response pathways and oncogenes, down-regulation of tumor suppressor genes, cell and tissue damage, and contribute to tumor initiation, promotion, and progression. However, the precise molecular links between inflammation and carcinogenesis remain to be clarified (1, 2).In the colon, alterations in the physiological balance between the diverse and abundant microbiota (w10 12 organisms per gram feces) and the host are a common source of inflammation. Bacteroides spp comprise a significant proportion of colonic commensal bacteria and members of this group include symbionts and the leading human anaerobic pathogen, Bacteroides fragilis. Enterotoxigenic B. fragilis (ETBF) represent a molecular subtype characterized by a single unique virulence determinant, the production and secretion of a 20-kDa metalloprotease enterotoxin (B. fragilis toxin; BFT). ETBF have been epidemiologically associated with acute diarrheal diseases in humans and livestock, inflammatory bowel diseases (IBD), and colorectal cancer (reviewed in ref.3). Exposure of intestinal epithelial cell lines to BFT results in cleavage of the cell adhesion and tumor suppressor protein E-cadherin, ...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Goodwin¹,

Shields²,

Wu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

501

353

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“…Direct indication of a role for GPx genes in carcinogenesis was provided by a study in which double-knockout mice for GPx-1 and GPx-2 genes developed ileal tumors associated with bacteria-induced intestinal inflammation. This antitumorigenic involvement of GPx in intestinal cancers was attributed to their antioxidant ability to quench inflammation-related increases in hydroperoxide concentrations in the gut (30).…”

Section: Discussionmentioning

confidence: 99%

Selenoprotein deficiency accelerates prostate carcinogenesis in a transgenic model

Diwadkar‐Navsariwala

Prins²,

Swanson

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

130

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Considerable animal and human data have indicated that selenium is effective in reducing the incidence of several different types of cancer, including that of the prostate. However, the mechanism by which selenium inhibits carcinogenesis remains unknown. One possibility is that dietary selenium influences the levels of selenium-containing proteins, or selenoproteins. Selenoproteins contain selenium in the form of selenocysteine and perform a variety of cellular functions, including antioxidant defense. To determine whether the levels of selenoproteins can influence carcinogenesis independent of selenium intake, a unique mouse model was developed by breeding two transgenic animals: mice with reduced selenoprotein levels because of the expression of an altered selenocysteine-tRNA (i 6 A ؊ ) and mice that develop prostate cancer because of the targeted expression of the SV40 large T and small t oncogenes to that organ [C3(1)͞Tag]. The resulting bigenic animals (i 6 A ؊ ͞Tag) and control WT͞Tag mice were assessed for the presence, degree, and progression of prostatic epithelial hyperplasia and nuclear atypia. The selenoprotein-deficient mice exhibited accelerated development of lesions associated with prostate cancer progression, implicating selenoproteins in cancer risk and development and raising the possibility that selenium prevents cancer by modulating the levels of these selenoproteins.cancer ͉ selenium

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“…One line of evidence supporting a cancer preventive role of GPx2 comes from the finding that GPx2 gene expression is under control of the antioxidant response transcription factor Nrf2. In addition, mice lacking the GPx2 gene are characterized by an increased sensitivity to UV-induced skin cancer development (363), whereas the double GPx1/GPx2 knockout mice demonstrated the development of spontaneous colitis and intestinal cancer (64). However, expression of GPx2 has also been shown to be regulated by the Wnt pathway, which is involved in activation of cellular proliferation, and knockdown of GPx2 in rat and human cancer cells resulted in significant growth inhibition (263) and induction of apoptosis (375).…”

Section: Selenoprotein Functionmentioning

confidence: 99%

Selenoproteins: Molecular Pathways and Physiological Roles

Labunskyy

Hatfield

Gladyshev³

2014

Physiological Reviews

1,060

835

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Selenium is an essential micronutrient with important functions in human health and relevance to several pathophysiological conditions. The biological effects of selenium are largely mediated by selenium-containing proteins (selenoproteins) that are present in all three domains of life. Although selenoproteins represent diverse molecular pathways and biological functions, all these proteins contain at least one selenocysteine (Sec), a seleniumcontaining amino acid, and most serve oxidoreductase functions. Sec is cotranslationally inserted into nascent polypeptide chains in response to the UGA codon, whose normal function is to terminate translation. To decode UGA as Sec, organisms evolved the Sec insertion machinery that allows incorporation of this amino acid at specific UGA codons in a process requiring a cis-acting Sec insertion sequence (SECIS) element. Although the basic mechanisms of Sec synthesis and insertion into proteins in both prokaryotes and eukaryotes have been studied in great detail, the identity and functions of many selenoproteins remain largely unknown. In the last decade, there has been significant progress in characterizing selenoproteins and selenoproteomes and understanding their physiological functions. We discuss current knowledge about how these unique proteins perform their functions at the molecular level and highlight new insights into the roles that selenoproteins play in human health.

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Bacteria-Induced Intestinal Cancer in Mice with DisruptedGpx1andGpx2Genes

Cited by 275 publications

References 61 publications

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Selenoprotein deficiency accelerates prostate carcinogenesis in a transgenic model

Selenoproteins: Molecular Pathways and Physiological Roles

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