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)

The cDNA sequences of thioredoxin obtained by PCR cloning from human colon cancer cells, human lymphoblastoid cells, and human liver have been found to be identical with the cDNA sequence reported for the autocrine growth factor, human adult T-cell leukemia derived factor (ADF). Recombinant human thioredoxin was 95% reduced by dithiothreitol and was a substrate for reduction by human thioredoxin reductase. Human non-small cell primary lung tumors from subjects who were not cigarette smokers at the time of surgery showed significantly increased levels of thioredoxin mRNA compared to thioredoxin mRNA in paired normal human lung tissue. Subjects who were smokers did not show a significant increase in lung tumor thioredoxin mRNA. The results of the study show that human thioredoxin and ADF are identical species and suggest that there may be increased production of thioredoxin (ADF) by some human cancers.
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PMID:The predicted amino acid sequence of human thioredoxin is identical to that of the autocrine growth factor human adult T-cell derived factor (ADF): thioredoxin mRNA is elevated in some human tumors. 804 54

Thioredoxin and thioredoxin reductase are redox proteins that have been implicated in the control of cell proliferation and transformation. We report the levels and activity of these proteins and their mRNAs in human primary tumors and tumor cell lines. Half of human primary colorectal carcinomas (5/10) examined had increased thioredoxin mRNA, of 3- to over 100-fold, compared to adjacent normal colonic mucosa from the same subject. Thioredoxin reductase protein and activity were increased an average of 2-fold in human colorectal tumors compared to normal mucosa. A number of human hematologic and solid tumor cell lines were studied and showed a 10-fold range of thioredoxin mRNA and a 23-fold range of thioredoxin reductase mRNA. Increased proliferation and hypoxia are factors that might contribute to the increased expression in solid tumors. We found that serum stimulation of growth arrested MCF-7 breast cancer cells caused a 59% increase in thioredoxin mRNA and a 62% increase in thioredoxin reductase mRNA by 24 hours. Exposure of HT-20 colon cancer cells to hypoxia resulted in a 14-fold increase in thioredoxin mRNA by 16 hours, and a transient 4-fold increase in thioredoxin reductase mRNA at 1 hour that had returned to control levels by 8 hours. Cancer cells were found to release thioredoxin into the medium at rates between 1 to 2 pmole/10(6) cells/3 hours. The rate of secretion was not, however, related to cellular-levels of thioredoxin. The results of the study show that the expression of thioredoxin and thioredoxin reductase are increased several fold in some human solid tumors compared to normal tissue. Secretion of thioredoxin, which is known to have a direct growth stimulating activity, by human tumor cells might lead to the stimulation of cancer cell growth.
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PMID:Thioredoxin and thioredoxin reductase gene expression in human tumors and cell lines, and the effects of serum stimulation and hypoxia. 904 7

Selenium (Se) is an essential trace element and has been reported to decrease the incidence of some human cancers. We have investigated the effects of Se on thioredoxin reductase, a selenocysteine containing flavoenzyme, in HT-29 human colon cancer cells grown in serum-free medium. Sodium selenite and other Se containing compounds produced a time and concentration dependent increase in intracellular thioredoxin reductase activity and protein levels. Selenite was the most active of the Se compounds examined: 1 microM selenite produced a 28-fold increase in thioredoxin reductase activity by 1 day and 10 microM selenite over a 60-fold increase by 5 days. The activity of a related non-selenocysteine containing flavoenzyme glutathione reductase was not increased by selenite. Selenite, but not the other Se containing compounds inhibited cell growth at concentrations above 2 microM. The results show that Se can produce large increases in cell thioredoxin reductase activity.
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PMID:Cellular thioredoxin reductase activity is regulated by selenium. 941 75

There is strong evidence that selenium protects against certain human cancers, but the underlying mechanism is unknown. Glutathione peroxidase (GPX1) and thioredoxin reductase (TR), the most abundant antioxidant selenium-containing proteins in mammals, have been implicated in this protection. We analyzed the expression of TR and GPX1 in the following model cancer systems: (1) liver tumors in TGFalpha/c-myc transgenic mice; (2) human prostate cell lines from normal and cancer tissues; and (3) p53-induced apoptosis in a human colon cancer cell line. TR was induced while GPX1 was repressed in malignancies relative to controls in transgenic mice and prostate cell lines. In the colon cell line, p53 expression resulted in elevated GPX1, but repressed TR. The data indicate that TR and GPX1 are regulated in a contrasting manner in the cancer systems tested and reveal the p53-dependent regulation of selenoprotein expression. The data suggest that additional studies on selenoprotein regulation in different cancers are required to evaluate future implementation of selenium as a dietary supplement in individuals at risk for developing certain cancers.
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PMID:Contrasting patterns of regulation of the antioxidant selenoproteins, thioredoxin reductase, and glutathione peroxidase, in cancer cells. 979 1

There is experimental and epidemiological evidence for an association between low selenium levels and gastrointestinal cancer incidence, prevalence, and mortality. To identify targets for selenium supplementation in the human digestive tract, we examined mRNA expression of various selenocysteine-containing proteins in normal mucosa biopsy specimens. Tissue samples from the esophagus and from different sites of the stomach, small bowel, and colon were obtained during endoscopies of the upper and lower gastrointestinal tract. Northern blot analyses revealed a lack of cytosolic glutathione peroxidase mRNA but a differential mRNA expression pattern of gastrointestinal and plasma glutathione peroxidase, selenoprotein P, and thioredoxin reductase. Glutathione peroxidase and thioredoxin reductase activities were detected in the mucosa of all biopsies, but the differential pattern did not reflect the differential mRNA steady-state levels. In addition to gastrointestinal glutathione peroxidase, which was found to play a role in colon cancer resistance, we identified further gastrointestinal selenoproteins, which may be involved in gastrointestinal cell defense and cell differentiation.
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PMID:Expression pattern of gastrointestinal selenoproteins--targets for selenium supplementation. 991 13

Multiple components of broccoli, such as sulforaphane (Sf) and phenolic acids, may inhibit cancer. Additionally, broccoli can accumulate selenium (Se), and Se has been demonstrated to reduce the risk of cancer. Studies were conducted to determine whether enhancement of broccoli with Se would produce a plant with superior health benefits. Although increasing the concentration of Se in broccoli from <1.0 to >800 microg/g resulted in inhibition of colon cancer in rats, it also decreased the Sf content by >80% and inhibited production of most phenolic acids. The inclusion of Se-enriched broccoli in the diet of rats induced the activity of the selenoprotein thioredoxin reductase beyond the maximum activity induced by Se alone. These results emphasize the complex interactions of bioactive chemicals in a food; attempts to maximize one component may affect accumulation of another, and consumption of high amounts of multiple bioactive compounds may result in unexpected metabolic interactions within the body.
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PMID:Selenium enrichment of broccoli: interactions between selenium and secondary plant compounds. 1586 10

Selenium has cancer protective effects in a variety of experimental systems. Currently, it is not known whether selenoproteins or low molecular weight selenocompounds are responsible for this activity. To evaluate the contribution of selenoproteins to the cancer protective effects of selenium, we used transgenic mice that carry a mutant selenocysteine transfer RNA gene, which causes reduced selenoprotein synthesis. Selenium homeostasis was characterized in liver and colon of wild-type and transgenic mice fed selenium-deficient diets supplemented with 0, 0.1, or 2.0 microg selenium (as selenite)/g diet. (75)Se-labeling, Western blot analysis, and enzymatic activities revealed that transgenic mice have reduced (P < 0.05) liver and colon glutathione peroxidase expression, but conserved thioredoxin reductase expression compared with wild-type mice, regardless of selenium status. Transgenic mice had more (P < 0.05) selenium in the nonprotein fraction of the liver and colon than wild-type mice, indicating a greater amount of low molecular weight selenocompounds. Compared with wild-type mice, transgenic mice had more (P < 0.05) azoxymethane-induced aberrant crypt formation (a preneoplastic lesion for colon cancer). Supplemental selenium decreased (P < 0.05) the number of aberrant crypts and aberrant crypt foci in both wild-type and transgenic mice. These results provide evidence that a lack of selenoprotein activity increases colon cancer susceptibility. Furthermore, low molecular weight selenocompounds reduced preneoplastic lesions independent of the selenoprotein genotype. These results are, to our knowledge, the first to provide evidence that both selenoproteins and low molecular weight selenocompounds are important for the cancer-protective effects of selenium.
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PMID:Both selenoproteins and low molecular weight selenocompounds reduce colon cancer risk in mice with genetically impaired selenoprotein expression. 1661 22

Previous studies demonstrate that the covalent modification of thioredoxin reductase (TrxR) by both endogenous and exogenous electrophiles results in disruption of the conformation of the tumor suppressor protein p53. Here we report that the loss of normal cellular TrxR enzymatic activity by electrophilic modification or deletion of the C-terminal catalytic selenocysteine residue has functional consequences that are distinct from those resulting from depletion of TrxR protein in human RKO colon cancer cells. A thorough kinetic analysis was performed on purified TrxR in order to characterize the mechanism of its inhibition by electrophiles. Furthermore, electrospray mass spectrometry confirmed the alkylation of TrxR by lipid electrophiles and liquid chromatography-mass spectrometry/mass spectrometry identified the C-terminus as one target for alkylation. Then the consequences of TrxR modification by electrophiles on p53 conformation, transactivation and apoptosis were compared and contrasted with the effects of depletion of TrxR protein by treatment of cells with small interfering RNA directed against TrxR1. We found that cells depleted of TrxR were actually less sensitive to electrophile-induced disruption of p53 conformation and apoptosis than were cells expressing normal levels of TrxR. When RKO cells depleted of wild-type TrxR were transfected with C-terminal mutants of TrxR lacking the catalytic selenocysteine, p53 was found to be conformationally deranged, similar to cells treated with electrophiles. These results lead us to conclude that C-terminal modification of TrxR is both necessary and sufficient for the disruption of p53 and for the induction of apoptosis. Endogenous lipid electrophiles have been our primary focus; however, metabolic activation of hormones can generate endogenous mutagens, and we demonstrate that estrone-quinone attenuates p53 function in human MCF7 cells.
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PMID:Thioredoxin reductase is required for the inactivation of tumor suppressor p53 and for apoptosis induced by endogenous electrophiles. 1677 82

Our previous studies have shown that selenium (Se) is protective against dimethylhydrazine (DMH)-induced preneoplastic colon cancer lesions, and protection against DNA damage has been hypothesized to be one mechanism for the anticancer effect of Se. The present study was designed to determine whether dietary selenite affects somatic mutation frequency in vivo. We used the Big Blue transgenic model to evaluate the in vivo mutation frequency of the cII gene in rats fed either a Se-deficient (0 microg Se/g diet) or Se-supplemented diet (0.2 or 2 microg Se/g diet; n = 3 rats/diet in experiment 1 and n = 5 rats/group in experiment 2) and injected with DMH (25 mg/kg body weight, i.p.). There were no significant differences in body weight between the Se-deficient and Se-supplemented (0.2 or 2 microg Se/g diet) rats, but the activities of liver glutathione peroxidase and thioredoxin reductase and concentration of liver Se were significantly lower (p < 0.0001) in Se-deficient rats compared to rats supplemented with Se. We found no effect of dietary Se on liver 8-hydroxy-2'-deoxyguanosine. Gene mutation frequency was significantly lower in liver (p < 0.001) than that of colon regardless of dietary Se. However, there were no differences in gene mutation frequency in DNA from colon mucosa or liver from rats fed the Se-deficient diet compared to those fed the Se-supplemented (0.2 or 2 microg Se/g diet) diet. Although gene mutations have been implicated in the etiology of cancer, our data suggest that decreasing gene mutation is not likely a key mechanism through which dietary selenite exerts its anticancer action against DMH-induced preneoplastic colon cancer lesions in a Big Blue transgenic rat model.
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PMID:High dietary intake of sodium selenite does not affect gene mutation frequency in rat colon and liver. 1926 1

The relationship between selenium and cancer is complex because individuals with low serum selenium levels benefit from selenium supplementation, but those with high serum selenium levels are at increased risk for other diseases. This suggests that the use of selenocompounds might be limited to particular circumstances, such as adjuvant therapy. A contributor to this dichotomy may be the activity of certain selenium containing enzymes like the cytosolic thioredoxin reductase (TR1). We evaluated the cellular response to select selenocompounds that have anticancer activity when TR1 was attenuated by siRNA in RKO colon cancer cells. Methylseleninic acid (MSA), which is a substrate for TR1, enhanced cytotoxicity to colon cancer cells when TR1 was attenuated. MSA induced stress in the endoplasmic reticulum, as measured by GRP78 protein levels. However, this pathway did not appear to account for the change in cytotoxicity when TR1 was attenuated. Instead, knockdown of the cytosolic TR plus incubation with MSA increased autophagy, as measured by LC3B cleavage, and apoptosis, as measured by Annexin V and mitochondrial dysfunction. Therefore, the use of selenocompounds with anticancer activity, like MSA, might be utilized most effectively with agents that targets TR1 in chemotherapeutic applications.
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PMID:Thioredoxin reductase 1 ablation sensitizes colon cancer cells to methylseleninate-mediated cytotoxicity. 1978 97


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