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: Tony W H Li, Heping Yang, Hui Peng, Meng Xia, José M Mato, Shelly C Lu
• Journal: Carcinogenesis (Carcinogenesis) Vol. 33 Issue 2 Pg. 427-35 (Feb 2012) ISSN: 1460-2180 [Electronic] England
• PMID: 22159228 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• NF-kappa B
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Tumor Necrosis Factor-alpha
• beta Catenin
• Interleukin-10
• S-Adenosylmethionine
• Dextran Sulfate
• S-Adenosylhomocysteine
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Purine-Nucleoside Phosphorylase
• 5'-methylthioadenosine phosphorylase
• Proto-Oncogene Proteins c-akt
• Azoxymethane

Topics

• Animals
• Apoptosis (drug effects)
• Azoxymethane (adverse effects)
• Cell Proliferation (drug effects)
• Cell Transformation, Neoplastic (metabolism, pathology)
• Chemoprevention (methods)
• Colonic Neoplasms (chemically induced, drug therapy, metabolism, pathology)
• Dextran Sulfate
• Inflammation (metabolism, pathology)
• Interleukin-10 (metabolism)
• Interleukin-6 (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• NF-kappa B (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Purine-Nucleoside Phosphorylase (pharmacology)
• S-Adenosylhomocysteine (metabolism)
• S-Adenosylmethionine (pharmacology)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Transcriptional Activation (drug effects)
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (metabolism)
• beta Catenin (metabolism)