ABSTRACT
SCOPE: Previous studies have shown that vitamin B6 supplementation suppresses the development of colonic aberrant crypt foci (ACF), precursor lesions of colon cancer, and cell proliferation in mice receiving the colonic carcinogen, azoxymethane (AOM). This study investigated the molecular mechanism of these effects of dietary vitamin B6. METHODS AND RESULTS: To date, the mechanism by which ACFs develop is not yet fully understood. In a search for factors that play a critical role during ACF development, we examined colon gene expression during early stage of ACF development in AOM-treated mice using DNA microarray analysis. AOM treatment significantly upregulated mRNA closely related to mast cell and cytotoxic T-cell activity. This study also investigated the effect of vitamin B6 supplementation on colon gene expression in AOM-treated mice. We found that vitamin B6 supplementation downregulates Cd8a and Ccl8 mRNA expression, suggesting these candidate genes may play a protective role against colonic ACF development. Furthermore, we examined genomic affects of dietary vitamin B6, and showed that Reg3γ mRNA expression in colons is downregulated by vitamin B6. CONCLUSION: This study provides an insight into the genomic activities of dietary vitamin B6 that may be protective against colon tumor development.
Subject(s)
Aberrant Crypt Foci/genetics , Colon/drug effects , Colonic Neoplasms/genetics , Dietary Supplements , Gene Expression Regulation, Neoplastic , Vitamin B 6/administration & dosage , Aberrant Crypt Foci/pathology , Aberrant Crypt Foci/prevention & control , Animals , Azoxymethane/toxicity , CD8 Antigens/genetics , CD8 Antigens/metabolism , Cell Proliferation/drug effects , Chemokine CCL8/genetics , Chemokine CCL8/metabolism , Colon/metabolism , Colon/pathology , Colonic Neoplasms/pathology , Colonic Neoplasms/prevention & control , Down-Regulation , Male , Mice , Mice, Inbred ICR , Oligonucleotide Array Sequence Analysis , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
SCOPE: Previous reports in the areas of animal studies and, recently epidemiology, have linked anti-tumorigenic and anti-inflammatory effects to dietary vitamin B6. This study investigated the molecular mechanism of these effects of vitamin B6. METHODS AND RESULTS: DNA microarray analysis was used to obtain information on changes in colon gene expression from vitamin B6 (pyridoxine) repletion in vitamin B6-deficient rats. Pyridoxine supplementation down-regulated the inflammatory molecule, serine protease inhibitor clade A member 3 (SPI-3) mRNA expression in the colon. This study also showed that tumor necrosis factor α (TNF-α) induced SPI-3 mRNA expression in HT-29 human colon cancer cells, and vitamin B6 (pyridoxal hydrochloride) pretreatment of HT-29 cells inhibited TNF -induced mRNA expression of SPI-3. Vitamin B6 inhibited TNF-α-induced NF-κB activation via suppression of IκBα degradation in HT-29 cells. HT-29 cells stably expressing epitope-tagged ubiquitin were generated and vitamin B6 pretreatment was shown to inhibit ubiquitination of the IkB protein in response to TNF-α-i. CONCLUSION: Vitamin B6 suppressed SPI-3 expression in the colon of rats and in TNF-α-stimulated HT-29 cells. Further, this study showed a possible role of vitamin B6 in the regulation of protein ubiquitination.
Subject(s)
Acute-Phase Proteins/metabolism , Anticarcinogenic Agents/metabolism , Colon/metabolism , Serpins/metabolism , Vitamin B 6/metabolism , Acute-Phase Proteins/genetics , Animals , Colon/drug effects , Colon/immunology , Colonic Neoplasms/etiology , Colonic Neoplasms/metabolism , Colonic Neoplasms/prevention & control , Gene Expression Regulation/drug effects , HT29 Cells , Humans , I-kappa B Proteins/metabolism , Male , NF-KappaB Inhibitor alpha , Oligonucleotide Array Sequence Analysis , RNA, Messenger/metabolism , Rats , Rats, Wistar , Recombinant Proteins/pharmacology , Serpins/genetics , Tumor Necrosis Factor-alpha/pharmacology , Ubiquitination , Vitamin B 6/therapeutic use , Vitamin B 6 Deficiency/drug therapy , Vitamin B 6 Deficiency/physiopathologyABSTRACT
We previously demonstrated that vitamin B6 suppresses tumorigenesis in the colon of mice and exerts an anti-inflammatory effect through the inhibition of NF-κB activation. As these effects resemble the pharmacological properties of thiazolidinedione (TZD), a synthetic peroxisome proliferator-activated receptor-γ (PPARγ) ligand, this study was designed to examine the effect of vitamin B6 on the activation of PPARγ and adipogenesis in 3T3-L1 adipocyte cells. Pyridoxal 5'-phosphate (PLP), one of the vitamin B6 derivatives, was shown to promote adipogenesis in the 3T3-L1 adipocytes. In addition, PLP specifically induced mRNA expression of PPARγ target genes in the 3T3-L1 adipocytes and enhanced the lipid accumulation and adipocyte fatty acid-binding protein (aP2) mRNA expression in NIH3T3 cells stably expressing PPARγ. Furthermore, the administration of vitamin B6 increased the expression of aP2 mRNA in mouse adipose tissues. Collectively, these observations suggest a novel function of vitamin B6 as an activator for PPARγ, which may contribute to the anti-tumor and anti-inflammatory effects of vitamin B6.
