Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In the present paper, the regulation of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, acylcoenzyme A cholesterol acyltransferase (ACAT) and low-density lipoprotein (LDL) binding was studied in the human colon cancer carcinoma cell line Caco-2. LDL down-regulated HMG-CoA reductase activity in a dose-dependent fashion to a minimum of 28% of control at 200 micrograms/ml and LDL binding to 52% of control. The activity of ACAT was stimulated by LDL. High-density lipoprotein 3 (HDL3) increased HMG-CoA reductase activity, whereas cholesteryl ester formation was slightly decreased. Inhibition of the endogenous cholesterol biosynthesis by mevinolin increased both LDL binding and activity of HMG-CoA reductase. This effect was reversed by the addition of mevalonolactone but not by LDL. It is concluded that regulation of HMG-CoA reductase and LDL binding is subject to the availability of non-sterol products of mevalonic acid and of exogenous cholesterol. ACAT is regulated mainly by the level of its substrate cholesterol.
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PMID:Regulation of cholesterol metabolism and low-density lipoprotein binding in human intestinal Caco-2 cells. 163 21

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, pravastatin (Pr) and simvastatin (Si), suppressed 1,2-dimethylhydrazine (DMH)-induced colon cancer development in female ICR mice. All mice received an i.p. injection of 10 mg DMH/kg body wt once weekly for 15 weeks. Pr was administered at 0.01, 0.005 and 0.001% levels in drinking water, and Si at 0.01 and 0.002% levels in the diet. All animals had access to Pr or Si throughout the experiments which were terminated at weeks 25 or 30. Histologically most of the tumors were well-differentiated adenocarcinomas. The incidence of colon tumors examined at weeks 25 or 30 was reduced by 67% in the 0.01% Pr group, by 30% in the 0.005% Pr and 0.01% Si groups, and by 24% in the 0.001% Pr and 0.002% Si groups, compared with their respective controls. However, the differences did not reach statistical significance. The number of tumors per mouse was significantly reduced in all groups administered Pr and Si except the 0.001% Pr group as compared to their respective controls. The results from those three independent experiments seem to suggest that HMG-CoA reductase inhibitors may prevent colon tumorigenesis in laboratory animal model.
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PMID:Prevention of 1,2-dimethylhydrazine-induced colon tumorigenesis by HMG-CoA reductase inhibitors, pravastatin and simvastatin, in ICR mice. 792

Depletion of mevalonic acid (MVA), obtained by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase using lovastatin, depressed the biosynthesis of dolichyl-phosphate and the rate of N-linked glycosylation and caused growth arrest in the melanoma cell line SK-MEL-2. The growth arrest was partially prevented by addition of high concentrations of insulin-like growth factor-1 (IGF-1) to the cells, indicating that MVA depletion may inhibit cell growth through decreasing the number of IGF-1 receptors (IGF-1R) at the cell surface. Such a decrease in receptor number might be a result of a lowered translocation of de novo synthesized receptors to the cell membrane which in turn might be a result of a decreased N-linked glycosylation of the receptor proteins. We could also demonstrate that IGF-1R became underglycosylated and that the amount of de novo synthesized IGF-1R proteins at the cell membrane was drastically decreased upon MVA depletion. Analysis of receptor proteins cross-linked with IGF-1, as well as binding assays and immunocytostaining confirmed that the number of functional membrane-bound IGF-1R was substantially reduced. The N-linked glycosylation and the expression of de novo synthesized IGF-1R proteins at the cell surface as well as the number of IGF-1 binding sites were completely restored upon replenishment of MVA. These effects of MVA were efficiently abrogated by the glycosylation inhibitor tunicamycin. The translocation of IGF-1R to the cell membrane was shown to take place just prior to initiation of DNA synthesis in arrested cells stimulated with MVA. Additionally, there was a clear correlation between IGF-1 binding and initiation of DNA synthesis with regard to the MVA dose requirement. It was confirmed that inhibition of HMG-CoA reductase activity and N-linked glycosylation also depressed the expression of functional IGF-1R in other cell types (i.e. hepatoblastoma cells and colon cancer cells). Our data suggest that this mechanism is involved in MVA-regulated cell growth.
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PMID:Mevalonic acid is limiting for N-linked glycosylation and translocation of the insulin-like growth factor-1 receptor to the cell surface. Evidence for a new link between 3-hydroxy-3-methylglutaryl-coenzyme a reductase and cell growth. 866 39

Tumors derived from the colonic epithelium exhibit cholesterol metabolism which is clearly different from that in fibroblasts, hepatocytes, adrenals, and ovaries. In hepatocytes and fibroblasts MEV inhibition of the rate limiting step in cholesterol synthesis HMG Co A reductase can be overcome by the uptake of LDL. Colon cancer cells however do not overcome MEV inhibition by LDL uptake but rather exhibit further growth suppression Mevinolin (Mevacor), a drug used to lower serum cholesterol levels has the advantage of accumulating in the liver to approximately 95% with the first pass. A small but variable percentage of non-sterol precursors may escape inhibition and be utilized for other pathways in the isoprenylation of certain proteins, among them members of the ras family. Mutated ras, an oncogene, is found in 40-50% of colon tumors and the expression of a functional gene product is dependent on isoprenylation for anchorage to the tumor cell membrane. d-Limonene, a relatively non-toxic monoterpene found in orange skin oil, selectively inhibits isoprenylation and also accumulates to some extent in the liver. It was hypothesized that the differences in mevalonate metabolism between hepatocytes and colon tumor cells could provide a chemotherapeutic advantage in which MEV and/or d-limonene could effectively inhibit cholesterol synthesis and post-translational modification of proteins with non-sterol cholesterol precursors in colon tumor derived hepatic metastases and thus inhibit their growth. Since each drug affects aspects of mevalonate synthesis at different points, the effects of the combination of their agents on inhibiting tumor metastases was investigated to ascertain if these could be additive. In tissue culture, MEV and d-limonene significantly inhibited the growth of CT-26, a murine transplantable colon tumor. Cholesterol synthesis assessed in these cells indicated that in lipid deficient media the following additions-25-hydroxycholesterol, and LDL significantly reduced cholesterol synthesis. Conversely, perillyl alcohol increased cholesterol synthesis 2.5 fold. In cells cultured in FBS based medium, which have an FBS control, MEV treatment reduced cholesterol synthesis to 65% of control. Perillyl alcohol increased synthesis 1.4 fold and when given in conjunction with MEV, it abolished the effects of this inhibitor. In isoprenylation studies of 14C-mevalonate incorporation into proteins, MEV impaired isoprenylation by restricting synthesis of mevalonate derived intermediates. Results of CT-26 treatment with perillyl alcohol are inconsistent with its putative role as a protein isoprenylation inhibitor. The combination of these agents indicates an additive action which requires additional investigation to elucidate their mechanism(s). Dietary MEV and d-limonene were evaluated alone and in combination for their chemotherapeutic potential in a hepatic "metastasis" model. Using splenic colonization in which CT-26 was implanted into the spleen and ultimately seeded the liver, each of these compounds were found to inhibit the growth of resultant tumors both alone and in combination by approximately 80% versus controls at 35 days post-implantation. Assessment of HMGCoA reductase in liver and tumor indicated that these agents were effective in reaching these target sites. The findings to date indicate that while d-limonene and MEV may differentially affect the same pathway, and their individual actions may appear antagonistic in vitro, their overall action individually or together, appears promising as a chemotherapeutic modality for the possible management of hepatic metastases from colon cancer.
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PMID:Effects of monoterpenes and mevinolin on murine colon tumor CT-26 in vitro and its hepatic "metastases" in vivo. 888 30

Thioredoxin (TRX) is a widely distributed Mr 13,000 protein with a redox-active dithiol/disulfide in the active site. The TRX system, consisting of TRX, TRX reductase, and NADPH, has an intracellular reducing capacity. Another reducing capacity, glutathione (GSH), can be associated with cis-diaminedichloroplatinum (cDDP) resistance. Therefore, we examined the involvement of TRX in cDDP resistance using two cell lines designated St/DDP and HT/DDP, which were established from the human gastric cancer cell line St-4 and the colon cancer cell line HT-29. St/DDP and HT/DDP were seven and five times as resistant to cDDP as their parental lines, and the expression of TRX in these variants was increased by 2.5- and 2-fold, respectively. The expression of TRX in the complete revertant cells of St/DDP was reduced as low as that in St-4 cells. TRX reductase activity was also increased in St/DDP and HT/DDP, suggesting that activation of the TRX system was associated with in vitro-acquired cDDP resistance. Because cDDP is the first-line drug against ovarian cancer, we examined the expression of TRX in 11 human ovarian cancer cell lines not treated with cDDP in vitro. Positive correlation between TRX expression and cDDP resistance was observed in these cell lines (r = 0.76, P = 0.007). This correlation was comparable to that between GSH content and cDDP resistance (r = 0.69, P = 0.019). These results suggest a possible involvement of TRX, as well as GSH, in cDDP resistance.
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PMID:Increased expression of thioredoxin/adult T-cell leukemia-derived factor in cisplatin-resistant human cancer cell lines. 981 87

A network composed of activation and inactivation pathways to regulate mitomycin C (MMC) action is suggested to exist in human cancer cells. COLO201 colon cancer cells were stably transfected with human NQO1 cDNA that encodes NAD(P)H:quinone oxidoreductase (DT-diaphorase, DTD), and a clonal cell line with about 57-fold elevated DTD activity was obtained. Northern analysis revealed that expression of the NADPH:cytochrome P450 reductase (P450 reductase) gene was decreased in the transfectant, COLO201/NQO1, associated with the increase of NQO1 expression. Biochemical characterization of the cells showed a significant increase of the glutathione (GSH) content concomitantly with the decrease of the P450 reductase activity. As a result of these coordinated modulations, sensitivity of COLO201/NQO1 to MMC was not increased as compared to the parent cells. Analyses of inhibition by specific inhibitors of DTD, P450 reductase and glutathione S-transferase (GST) in 5 human colon cancer cell lines including the transfectant showed that DTD and P450 reductase play significant roles in MMC activation in cells with sufficiently high DTD activity and with marginal DTD activity, respectively. In contrast, GST appeared to participate in MMC inactivation in cells with a high level of GST activity. These results indicated that DTD, P450 reductase, GSH and GST may act together compensatively or competitively, depending on their levels in cells, to determine the cellular sensitivity to MMC.
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PMID:Regulatory network of mitomycin C action in human colon cancer cells. 1039 Oct 98

Beta-hydroxy-beta-methylglutaryl coA reductase inhibitors (HRIs) inhibit isoprenylation of several members of the Ras superfamily of proteins and therefore have important cellular effects, including the reduction of proliferation and increasing apoptosis. Significant toxicity at high doses has precluded the use of HRIs as a monotherapy for cancers. We therefore studied whether combinations of the HRI lovastatin with standard chemotherapeutic agents would augment apoptosis in colon cancer cells. In the colon cancer cell lines SW480, HCT116, LoVo, and HT29, lovastatin induced apoptosis with differing sensitivity. Pretreatment with lovastatin significantly increased apoptosis induced by 5-fluorouracil (5-FU) or cisplatin in all four cell lines. Lovastatin treatment resulted in decreased expression of the antiapoptotic protein bcl-2 and increased the expression of the proapoptotic protein bax. The addition of geranylgeranylpyrophospate (10 microM) prevented lovastatin-induced augmentation of 5-FU and cisplatin-induced apoptosis; mevalonate (100 microM) was partially effective, whereas cotreatment with farnesyl pyrophosphate (100 microM) had no effect. These data imply that lovastatin acts by inhibiting geranylgeranylation and not farnesylation of target protein(s). Our data suggest that lovastatin may potentially be combined with 5-FU or cisplatin as chemotherapy for colon cancers.
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PMID:Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. 1074 52

Epidemiologic studies of breast and pancreatic cancer in several Mediterranean populations have demonstrated that increased dietary intake of olive oil is associated with a small decreased risk, or no increased risk, of cancer, despite a high overall lipid intake. Experimental animal models in high dietary fat and cancer also indicate that olive oil either has no effect, or a protective effect, on the prevention of a variety of chemically induced tumors. As a working hypothesis, it is proposed that the high squalene content of olive oil, as compared to other human foods, is a major factor in the cancer-risk reducing effect of olive oil. Experiments in animal models suggest a tumor-inhibiting role for squalene. A mechanism is proposed for the tumor-inhibitory activity of squalene based on its known strong inhibitory activity of HMG-COA reductase catalytic activity in vivo, thus reducing farnesyl pyrophosphate (FPP) availability for "prenylation" of ras oncogene, which relocates this oncogene to cell membranes and is required for the signal-transducing function of ras. Reduction of mutated ras oncogene activation may be useful in breast and colon cancer and may be particularly applicable to pancreatic cancers that are strongly associated with ras oncogenes.
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PMID:Squalene, olive oil, and cancer risk. Review and hypothesis. 1066 94

Colorectal hyperplastic polyps are benign lesions that share many risk factors with colorectal adenomas and cancers. Low folate intakes are associated with an increased risk of colon cancer. The enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR) may be linked to DNA methylation and nucleotide synthesis and thus play a role in the etiology of colorectal neoplasia. We investigated an association between the common MTHFR polymorphism (C677T) and colorectal hyperplastic polyps within the Minnesota Cancer Prevention Research Unit case-control study. Cases (n = 200) were diagnosed with colonoscopically confirmed hyperplastic polyps; controls (n = 645) were derived from the same gastroenterology practice and were polyp-free at colonoscopy. Dietary intakes were estimated from a self-administered food-frequency questionnaire prior to colonoscopy. Multivariate adjusted odds ratios (ORs) and 95% confidence intervals for MTHFR status were 0.8 (0.6-1.2; CT versus CC wild-type) and 0.9 (0.5-1.6; TT versus CC). In subgroup analyses stratified on dietary intakes of folate, vitamin B12, vitamin B6, or methionine, those with the TT genotype and either low intakes of folate or vitamin B6 were at increased risk relative to those with normal or high vitamin intake. However, most 95% confidence intervals included 1.0, and no consistent trends were observed. In contrast to our findings on colorectal adenomas, increasing alcohol consumption was associated with an elevated risk of colorectal hyperplastic polyps, regardless of genotype. The MTHFR (C677T) variant genotype does not appear to be related to risk of colorectal hyperplastic polyps, and there is no convincing evidence that MTHFR shows a different relation to risk, dependent on dietary intakes of nutrients related to its pathway.
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PMID:Lack of association between the C677T MTHFR polymorphism and colorectal hyperplastic polyps. 1079 88

Mevastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. Butyrate, a short-chain fatty acid, reduces proliferation and induces differentiation of human colon cancer cells. The aim of our study was to determine the effect of mevastatin, alone or in combination with butyrate, on proliferation, the cell cycle and apoptosis in the human colorectal carcinoma cell line Caco-2. In this report we show that mevastatin combined with butyrate synergistically suppressed growth of Caco-2 cells in a dose- and time-dependent manner. In addition, incubation with mevastatin arrested cells in the G1 phase of the cell cycle after 24 h with a switch to the G2/M phase after 72 h. This was accompanied by a down-regulation of cyclin-dependent kinases (cdk) 4 and cdk 6 as well as cyclin D1, while cdk 2 and cyclin E protein levels remained unchanged during mevastatin treatment. Cell cycle inhibitors p21 and p27 were significantly upregulated by mevastatin. The proapoptotic properties of mevastatin were further enhanced by co-incubation with butyrate. Lastly, the effects of mevastatin could be reversed by addition of mevalonate, but not farnesyl- or geranylgeranylpyrophosphate, intermediate products of cholesterol synthesis, to the medium. These results suggest that HMG-CoA reductase inhibitors like mevastatin may enhance the antiproliferative effect of butyrate in colon cancer cells via induction of apoptosis together with a G0/G1 cell cycle arrest.
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PMID:HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2. 1140 50


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