title: Effects of S-adenosylmethionine and methylthioadenosine on inflammation-induced colon cancer in mice.
abstract: Chronic inflammation is an underlying risk factor for colon cancer. Tumor necrosis factor alpha (TNF-α) plays a critical role in the development of inflammation-induced colon cancer in a mouse model. S-adenosylmethionine (SAMe) and its metabolite methylthioadenosine (MTA) can inhibit lipopolysaccharide-induced TNF-α expression in macrophages. The aim of this work was to examine whether SAMe and MTA are effective in preventing inflammation-induced colon cancer and if so identify signaling pathways affected. Balb/c mice were treated with azoxymethane (AOM) and dextran sulfate sodium to induce colon cancer. Two days after AOM treatment, mice were divided into three groups: vehicle control, SAMe or MTA. Tumor load, histology, immunohistochemistry, gene and protein expression were determined. SAMe and MTA treatment reduced tumor load by ∼40%. Both treatments raised SAMe and MTA levels but MTA also raised S-adenosylhomocysteine levels. MTA treatment prevented the induction of many genes known to play pathogenetic roles in this model except for TNF-α and inducible nitric oxide synthase (iNOS). SAMe also had no effect on TNF-α or iNOS and was less inhibitory than MTA on the other genes. In vivo, both treatments induced apoptosis but inhibited proliferation, β-catenin, nuclear factor kappa B activation and interleukin (IL) 6 signaling. Effect of SAMe and MTA on IL-6 signaling was examined using Colo 205 colon cancer cells. In these cells, SAMe and MTA inhibited IL-6-induced IL-10 expression. MTA also inhibited IL-10 transcription and signal transducer and activator of transcription 3 activation. In conclusion, SAMe and MTA reduced inflammation-induced colon cancer and inhibited several pathways important in colon carcinogenesis.
authors.affiliation: Division of Gastroenterology and Liver Diseases, University of Southern California Research Center for Liver Diseases, University of Southern California-University of California, Los Angeles, CA 90033, USA.
authors.forename: Tony W H
authors.initials: TW
authors.lastname: Li
authors.forename: Heping
authors.initials: H
authors.lastname: Yang
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Meng
authors.initials: M
authors.lastname: Xia
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001397:Azoxymethane / Q000009:adverse effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D018890:Chemoprevention / Q000379:methods; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D016264:Dextran Sulfate; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011683:Purine-Nucleoside Phosphorylase / Q000494:pharmacology*; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D016753:Interleukin-10; D012436:S-Adenosylmethionine; D016264:Dextran Sulfate; D012435:S-Adenosylhomocysteine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D051057:Proto-Oncogene Proteins c-akt; D001397:Azoxymethane