Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selenium metabolism and polyamine biosynthesis are linked in their common requirement for S-adenosylmethionine. The effects of selenium supplementation (0.1 to 6.0 ppm) on growth, polyamine biosynthesis and S-adenosylmethionine were examined in two human colon cancer cell lines, WiDr and HT29. WiDr cells were very sensitive to selenium with a significant decrease in 3H-thymidine incorporation and cell number to doses above 0.25 ppm. HT29 cells were less sensitive. In HT29 cells, ornithine decarboxylase activity and its product putrescine decreased in parallel with the growth inhibitory effects of selenium. Similar changes were not noted in WiDr cells. Spermidine and spermine content were conserved in both cell lines exposed to cytotoxic doses of selenium. S-adenosylmethionine was increased in HT29 cells at cytotoxic doses of selenium (1.0 to 6.0 ppm).
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PMID:Effect of selenium on growth, S-adenosylmethionine and polyamine biosynthesis in human colon cancer cells. 831 17

C --> T transitions at CpG sites are the most prevalent mutations found in the p53 tumor suppressor gene in human colon tumors and in the germline (Li-Fraumeni syndrome). All of the mutational hot spots are methylated to 5-methylcytosine, and it has been hypothesized that the majority of these mutations are caused by spontaneous hydrolytic deamination of this base to thymine. We have previously reported that bacterial methyltransferases induce transition mutations at CpG sites by increasing the deamination rate of C --> U when the concentration of the methyl group donor S-adenosylmethionine (AdoMet) drops below its Km, suggesting an alternative mechanism to create these mutations. Unrepaired uracil pairs with adenine during replication, completing the C --> T transition mutation. To determine whether this mechanism could contribute to the development of human colon cancer, we examined the level of DNA (cytosine-5)-methyltransferase (MTase) expression, the concentration of AdoMet, and the activity of uracil-DNA glycosylase in human colon tissues, and searched for the presence of mutations in the MTase gene. Using reverse transcription-PCR methods, we found that average MTase mRNA expression levels were only 3.7-fold elevated in tumor tissues compared with surrounding normal mucosa from the same patient. Also, no mutations were found in conserved regions of the gene in 10 tumors sequenced. High-performance liquid chromatographic analysis of extracts from the same tissues showed that AdoMet concentrations were not reduced below the Km value for the mammalian enzyme, and the concentration ratio of AdoMet:S-adenosylhomocysteine, the breakdown product of AdoMet and the competitive MTase inhibitor, did not differ significantly. Finally, extracts from the tumor tissue efficiently removed uracil from DNA. Therefore, biochemical conditions favoring a mutagenic pathway of C --> U --> T were not found in a target tissue known to undergo a high rate of C --> T transitions at CpG sites.
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PMID:Mechanisms for the involvement of DNA methylation in colon carcinogenesis. 862 14

The efficacy of dietary selenium supplementation is currently being evaluated in intervention trials. However, the biological mechanisms underlying the cancer chemopreventive effects of selenium supplementation have yet to be elucidated. Selenium metabolism and polyamine biosynthesis are linked in their common requirement for S-adenosylmethionine. Selenomethionine was the predominant form of selenium in the dietary supplement, therefore we evaluated the anti-tumorigenic effects of selenomethionine. We found that selenomethionine inhibited tumor growth (both in A549 lung and HT29 colon cancer cells) in a dose-dependent manner. At 24 and 72 h, polyamine content of A549 and HT29 cancer cell lines was decreased at doses that inhibited 50% of normal growth. Selenomethionine treatment induced apoptosis in both cancer cell lines. Exogenous spermine administration, which replenishes intracellular polyamine levels, prevented selenomethionine induced apoptosis. Selenomethionine administration to the cancer cell lines increased the number of cells in metaphase. This cell cycle effect appeared to be reversed with the co-administration of selenomethionine and spermine. These data suggested that at least part of the anti-carcinogenic effects of selenium supplementation might be due to a depletion in polyamine levels. This depletion of polyamines leads to an induction in apoptosis and perturbations in the cell cycle.
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PMID:Involvement of polyamines in selenomethionine induced apoptosis and mitotic alterations in human tumor cells. 921 3

Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional and/or genetic disruptions in homocysteine metabolism. The most common genetic cause of hyperhomocysteinemia is the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. This variant, with mild enzymatic deficiency, is associated with an increased risk for neural tube defects and pregnancy complications and with a decreased risk for colon cancer and leukemia. Although many studies have reported that this variant is also a risk factor for vascular disease, this area of investigation is still controversial. Severe MTHFR deficiency results in homocystinuria, an inborn error of metabolism with neurological and vascular complications. To investigate the in vivo pathogenetic mechanisms of MTHFR deficiency, we generated mice with a knockout of MTHFR: Plasma total homocysteine levels in heterozygous and homozygous knockout mice are 1.6- and 10-fold higher than those in wild-type littermates, respectively. Both heterozygous and homozygous knockouts have either significantly decreased S-adenosylmethionine levels or significantly increased S-adenosylhomocysteine levels, or both, with global DNA hypomethylation. The heterozygous knockout mice appear normal, whereas the homozygotes are smaller and show developmental retardation with cerebellar pathology. Abnormal lipid deposition in the proximal portion of the aorta was observed in older heterozygotes and homozygotes, alluding to an atherogenic effect of hyperhomocysteinemia in these mice.
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PMID:Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. 1118 67

Folate is involved in the synthesis of nucleotides and amino acid metabolism such as methylation of homocysteine to methionine. Methionine is activated by adenosine triphosphate (ATP) to produce S-adenosylmethionine (SAM), the primary intracellular methyl donor. Thus, folate is essential for the synthesis, methylation, and repair of DNA. With regard to its biochemical function it has been hypothesized that a diminished folate status may contribute to carcinogenesis by alteration of gene expression and increased DNA damage. Animal and human studies support this hypothesis, particularly with respect to colorectal cancer. Epidemiological evidence for the association between folate status and cancer was first observed among ulcerative colitis patients. Several case-control studies demonstrated reduction in colorectal cancer risk with better folate status. Two large, prospective cohort studies support the concept that high folate intake is protective against colon cancer. In contrast to colorectal cancer, the potential association of folate status and risk has been less investigated in breast cancer. Recently, convincing epidemiological data establishing a positive effect of folate status on breast cancer risk were published. This review summarizes the epidemiological evidence for the association between folate status and colorectal and breast cancer risk. In addition, a short overview is given on the discussed mechanism(s) by which folate might be involved in carcinogenesis.
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PMID:Beneficial role for folate in the prevention of colorectal and breast cancer. 1169 47

A low intake of vegetables (but not fruit) is established as a risk factor for colon cancer. Although there are a multitude of active agents that may explain this, one important candidate is folate. Among studies specifically examining intake of folate derived from food and supplements, higher intake is generally associated with lower risk of both adenomas and cancer. Other nutrients associated with the folate pathway-methionine, vitamin B-6, vitamin B-12-or that impact the pathway-alcohol-have also been shown to influence risk in predictable ways. Polymorphisms in enzymes involved in the metabolism of folate also are associated with modification in risk, but essentially only in the presence of low intakes of folate and related nutrients. The consistency of the above evidence suggests that folate is an active agent, not just a marker for the intake of other effectors found in vegetables and multivitamin preparations. There are at least two mechanisms that may explain these findings: folate is central both to the provision of S-adenosylmethionine, the universal methyl donor, and to the provision of nucleotides for DNA synthesis and repair. Fortification of food with folate, as well as intake from multivitamin and pharmacological sources, may increasingly contribute to the primary prevention of colorectal neoplasia although it is possible that there is such a condition as having too much folate.
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PMID:Methyl supply, methyl metabolizing enzymes and colorectal neoplasia. 1216 2

Although a number of studies have suggested that diets with low intake of folate, an important methyl donor, are associated with increased risks of colon cancer and its precursor the adenomatous polyp, the underlying mechanisms are poorly understood. Dysregulation and instability of DNA methylation and alterations in the levels of the predominant DNA methylating enzyme, DNA (cytosine-5)-methyltransferase 1 (Dnmt1), have also been linked to tumorigenesis. We have used a combination of genetic and dietary manipulation to assess the effects of reduced Dnmt1 expression with and without folate deficiency on tumor induction in the Apc(Min) mouse. Apc(Min) mice with a reduction in Dnmt1 expression (Apc(Min/+)/Dnmt1(C/+)) had significantly lower tumor numbers than Apc(Min) mice with normal Dnmt1 (Apc(Min/+)/Dnmt1(+/+)). Dietary folate deficiency from weaning to 13 weeks of age did not affect tumor number or size in Apc(Min/+)/Dnmt(+/+) mice. However, in Apc(Min/+)/Dnmt1(C/+) mice with high baseline tumor numbers (41 +/- 4), folate deficiency was associated with a decreased absolute number of tumors (27 +/- 3), but a higher proportion of larger tumors as compared with mice on the control diet. In the repeat experiment, Apc(Min/+)/Dnmt1(C/+) mice had low baseline tumor numbers (20 +/- 2) and folate deficiency did not affect tumor number (23 +/- 4) or size as compared with the same mice on the control diet. These results suggest that, in the presence of Dnmt1 deficiency, the effects of folate deficiency on tumor number and size may depend on the stage of adenoma development when folate deficiency is initiated. We also show that folate deficiency with or without reductions in Dnmt1 did not affect overall genomic DNA methylation or the methylation levels of two candidate genes, E-cadherin or p53, in normal or neoplastic intestinal tissue. In conclusion, genetic deficiency in Dnmt1 with or without folate deficiency decreases tumor number in the Apc(Min) mouse model, but this effect may not be mediated by changes in SAM or SAH levels, nor by alterations in global methylation in the pre-neoplastic intestinal tissue.
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PMID:Impact of Dnmt1 deficiency, with and without low folate diets, on tumor numbers and DNA methylation in Min mice. 1253 47

Folate is an essential co-factor in the remethylation of homocysteine to methionine, thereby ensuring the supply of S-adenosylmethionine, the methyl group donor for most biological methylations, including that of DNA. Aberrant patterns and dysregulation of DNA methylation are consistent events in carcinogenesis and hence, DNA methylation is considered to be mechanistically related to the development of cancer. Folate deficiency appears to increase the risk of several malignancies, and aberrant DNA methylation has been considered to be a leading mechanism by which folate deficiency enhances carcinogenesis. Although diets deficient in methyl group donors (choline, folate, methionine and vitamin B12) have been consistently observed to induce DNA hypomethylation, the effect of an isolated folate deficiency on DNA methylation remains highly controversial and unresolved. Whether or not isolated folate deficiency can modulate DNA methylation is an important issue because it would establish a mechanistic link between folate deficiency and cancer. We examined the effects of isolated folate deficiency on methionine cycle intermediates, genomic and site-specific DNA methylation and DNA methyltransferase in an in vitro model of folate deficiency, using untransformed NIH/3T3 and CHO-K1 cells, and human HCT116 and Caco-2 colon cancer cells. Our data demonstrate that the effect of folate deficiency on the methionine cycle pathway and DNA methylation in these cells is highly complex and appears to depend on the cell type and stage of transformation, and may be gene and site-specific. The direction of changes of methionine cycle intermediates in response to folate deficiency is not uniformly consistent with the known biochemical effect of folate on the methionine cycle pathway. Moreover, the effect of folate deficiency on DNA methylation appears to be mediated by both methionine cycle intermediate-dependent and independent pathways.
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PMID:Cell and stage of transformation-specific effects of folate deficiency on methionine cycle intermediates and DNA methylation in an in vitro model. 1569 36

Low dietary folate intake is associated with an increased risk for colon cancer; however, relevant genetic animal models are lacking. We therefore investigated the effect of targeted ablation of two folate transport genes, folate binding protein 1 (Folbp1) and reduced folate carrier 1 (RFC1), on folate homeostasis to elucidate the molecular mechanisms of folate action on colonocyte cell proliferation, gene expression, and colon carcinogenesis. Targeted deletion of Folbp1 (Folbp1(+/-) and Folbp1(-/-)) significantly reduced (P < 0.05) colonic Folbp1 mRNA, colonic mucosa, and plasma folate concentration. In contrast, subtle changes in folate homeostasis resulted from targeted deletion of RFC1 (RFC1(+/-)). These animals had reduced (P < 0.05) colonic RFC1 mRNA and exhibited a 2-fold reduction in the plasma S-adenosylmethionine/S-adenosylhomocysteine. Folbp1(+/-) and Folbp1(-/-) mice had larger crypts expressed as greater (P < 0.05) numbers of cells per crypt column relative to Folbp1(+/+) mice. Colonic cell proliferation was increased in RFC1(+/-) mice relative to RFC1(+/+) mice. Microarray analysis of colonic mucosa showed distinct changes in gene expression specific to Folbp1 or RFC1 ablation. The effect of folate transporter gene ablation on colon carcinogenesis was evaluated 8 and 38 weeks post-azoxymethane injection in wild-type and heterozygous mice. Relative to RFC1(+/+) mice, RFC1(+/-) mice developed increased (P < 0.05) numbers of aberrant crypt foci at 8 weeks. At 38 weeks, RFC1(+/-) mice developed local inflammatory lesions with or without epithelial dysplasia as well as adenocarcinomas, which were larger relative to RFC1(+/+) mice. In contrast, Folbp1(+/-) mice developed 4-fold (P < 0.05) more lesions relative to Folbp1(+/+) mice. In conclusion, Folbp1 and RFC1 genetically modified mice exhibit distinct changes in colonocyte phenotype and therefore have utility as models to examine the role of folate homeostasis in colon cancer development.
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PMID:Folate transport gene inactivation in mice increases sensitivity to colon carcinogenesis. 1570 87

The folate antagonist methotrexate (MTX) inhibits synthesis of tetrahydrofolate (THF), pyrimidines and purines, and induces differentiation in several cell types. At 1 microM, MTX reduced proliferation and induced differentiation in HT29 colon cancer cells; the latter effect was augmented (P < 0.001) by thymidine (100 microM) but was reversed (P < 0.001) by the purines, hypoxanthine (Hx; 100 microM) and adenosine (100 microM). In contrast 5-fluoro-uracil (5-FU), a specific thymidylate synthase (TS) inhibitor, had no effect on differentiation, suggesting that MTX-induced differentiation is not due to a reduction in thymidine but to the inhibition of purine biosynthesis. Inhibition of cyclic AMP (cAMP) by RpcAMP (25 microM) further enhanced (P < 0.001) MTX induced differentiation, whereas the cAMP activator forskolin (10 microM) reversed (P < 0.001) MTX induced differentiation. These observations implicate a central role of adenosine and cAMP in MTX induced differentiation. By combining Western blot analysis with liquid chromatography-mass spectrometry (LC-MS)and HPLC analyses we also reveal both the expression and activity of key enzymes (i.e. methionine synthase (MS), s-adenosylhomocysteinase, cystathionine beta-synthase and ornithine decarboxylase) regulating methyl cycle, transsulfuration and polyamine pathways in HT29 colon cancer cells. At 1 microM, MTX induced differentiation was associated with a marked reduction in the intracellular concentrations of adenosine and, consequently, S-adenosylmethionine (SAM), S-adenosylhomocysteine, polyamines and glutathione (GSH). Importantly, the marked reduction in methionine that accompanied MS inhibition following MTX treatment was non-limiting with respect to SAM synthesis. Collectively, these findings indicate that the effects of MTX on cellular differentiation and single carbon metabolism are primarily due to the intracellular depletion of purines.
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PMID:Methotrexate induced differentiation in colon cancer cells is primarily due to purine deprivation. 1659 58


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