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)

Staurosporine (ST), a potent inhibitor of protein kinase C (PKC), was evaluated for its effect on the proliferation of HT-29 colon adenocarcinoma cells; PKC is associated with increased colon cell proliferation. ST inhibited cell proliferation in a time- and concentration-dependent manner by up to 90%. It also blocked the G2/M phase of the cell cycle and induced classical apoptosis (sub-diploid peak on flow cytometry, DNA ladder, and typical morphological changes). The kinetics of these changes suggest that low ST concentrations (2-20 nM) may act via a different mechanism from higher (100-1000 nM) ones. The role of ST, which is currently evaluated as an antitumor agent, in colon cancer requires further evaluation.
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PMID:Staurosporine inhibits the proliferation, alters the cell cycle distribution and induces apoptosis in HT-29 human colon adenocarcinoma cells. 891 70

During cancer progression, tumor cells interact with stromal cells. As a consequence, matrix metalloproteinases are produced that contribute to the degradation of the extracellular matrix. This study used coculture systems to investigate fibroblast interaction with three colon cancer cell lines isolated from a single patient. Cells from primary colorectal carcinoma, but not from corresponding liver or lymph node metastases, induced gelatinase B expression by fibroblasts of different tissue origin. Remarkably, direct cell-cell contact was required for this induction, which occurred at the pretranslational level (as revealed by Northern blot analysis) and was completely blocked by anti-beta1 integrin monoclonal antibody, but only partially blocked by anti-alpha5 or anti-alpha(v). Induction was also inhibited by cytochalasin D, staurosporine, or dexamethasone, suggesting the need, respectively, for an organized actin cytoskeleton, protein kinase C, and AP-1-driven gene transcription. Our data suggest that direct tumor-stromal cell contact is one inductive event involved in matrix metalloproteinase expression by stromal cells.
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PMID:Induction of fibroblast gelatinase B expression by direct contact with cell lines derived from primary tumor but not from metastases. 896 8

The objective of the present study was to examine the effect of modifying the fatty acid composition of membranes on cell growth and phosphoinositide specific phospholipase C (PLC) activity in HT-29 colon cancer cells. Cells were seeded at a density of 12 x 10(3) cells/cm2 and supplemented with 30 microM of either 18:0, 18:2 (n6) or 18:3 (n3) complexed to bovine serum albumin (BSA) in DMEM medium. Cell growth was followed for 12 days. The 18:0 supplemented cells (control) reached maximum growth at day nine which was greater than either 18:2 (n6) or 18:3 (n3) supplemented cells. There was no difference between the latter two groups in their growth. To investigate the fatty acid incorporation of the supplemented fatty acid and how they may influence composition in the cell membrane, we examined the fatty acid composition of each phospholipid (PL) species. Both phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were significantly influenced by the type of fatty acid supplemented. Supplementation with 18:0 resulted in HT-29 cell membranes having more monounsaturated fatty acids than the cells grown in the other fatty acids. Polyunsaturated fatty acid (PUFA) supplementation (both 18:2 and 18:3) resulted in the enrichment of PUFA in the PL fractions. Cells supplemented with 18:3 (n3) had the highest unsaturation index in membrane PE as compared to the other phospholipid species. PLC activity of the membranes was measured using PIP2 as a substrate in the presence of 15 micrograms alamethicin and 42 microM free calcium. The contribution of G protein to the activity of the enzyme was assessed using GTP gamma(S). PLC activity of HT-29 cells was 16% higher in the presence of GTP gamma(S) response. GTP gamma(S)-activated PLC activity of 18:3 (n3) supplemented cells was 81% of those supplemented with either 18:0 or 18:2 (n6) cells. It is concluded that the decrease in cell proliferation with supplementation with 18:3 (n3) may be mediated through its inhibitory effect on PLC, which provides the second messengers for protein kinase C (PKC) activation. PLC may be influenced by an increased unsaturation index of the PE fraction of the HT-29 tumor cell membranes.
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PMID:Effect of membrane lipid alteration on the growth, phospholipase C activity and G protein of HT-29 tumor cells. 898 25

In order to elucidate the influence of dietary constituents on colonic intracellular signal transduction, the effect of different fats on rat colonic epithelial protein kinase C (PKC) alpha (classical), delta (novel) and lambda-zeta (atypical) expression was determined in carcinogen-treated animals. Sprague-Dawley rats were provided with one of two fats (corn oil and fish oil); plus or minus the carcinogen azoxymethane (AOM) and killed at two time points (15 and 37 weeks) in a 2x2x2 factorial design. At 5 and 6 weeks of age, animals were injected s.c. with either AOM at a dose of 15 mg/kg body weight or saline once a week for 2 weeks and continued on the same diet until termination of the study. At 15 and 37 weeks after the second injection, 10 rats from each treatment group were killed. Colonic PKC alpha, delta and lambda-zeta steady-state protein and mRNA levels were determined using immunoblotting and relative quantitative polymerase chain reaction, respectively. Colonic mucosa from rats injected with AOM had significantly suppressed membrane and cytosolic PKC alpha and cytosolic lambda-zeta protein levels (P < 0.05) as compared to saline-injected control animals at both time points. In contrast, rats fed fish oil diets had significantly higher (P < 0.05) cytosolic PKC delta and lambda-zeta protein levels relative to animals fed corn oil diets. However, the effect of diet and AOM on the steady-state expression of PKC alpha, delta and zeta mRNA was not consistent with changes in the respective isozyme protein levels, suggesting regulation at the post-transcriptional level. These data demonstrate that dietary fish oil blocks the carcinogen-induced decrease in the steady-state levels of colonic mucosal PKC delta and lambda-zeta, which may in part explain why this fat source protects against colon cancer development.
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PMID:Dietary fish oil blocks carcinogen-induced down-regulation of colonic protein kinase C isozymes. 905 28

In contrast to most other systems, TPA induced TGc activity and protein in SW620 human colon carcinoma cells. This induction was accompanied by cell growth inhibition and increased apoptosis. The general protein kinase-C inhibitor GF-109203X blocked the induction of TGc by TPA, whereas the specific inhibitor of the PKC alpha isoform, the indocarbazole Go6976, reduced it by 40%. These PKC inhibitors had similar inhibitory effects on TPA increased apoptosis and inhibition of cell growth, suggesting that the observed actions of TPA are mediated by PKC, and a close connection between TGc activity, increased apoptosis and cell growth inhibition. We conclude that TPA may offer new approaches in the management of colon cancer cell growth.
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PMID:TPA induces transglutaminase C and inhibits cell growth in the colon carcinoma cell line SW620. 912 46

To elucidate the mechanisms by which dietary factors influence the risk of colon cancer, we investigated the effect of select dietary fats and fibers on atypical protein kinase C (PKC) lambda expression. Azoxymethane- and saline (control)-injected rats were fed diets containing either corn oil or fish oil (15 g/100 g) and either cellulose or pectin (6 g/100 g) and killed at two time points (15 and 37 wk) in a 2 x 2 x 2 x 2 factorial design. Colonic PKC lambda protein and mRNA levels were determined using immunoblotting and relative competitive polymerase chain reaction, respectively. Azoxymethane suppressed cytosolic PKC lambda protein levels compared with the saline controls at both time points, and this suppression was partially blocked by fish oil feeding at 15 wk and pectin at 37 wk. Also, at 15 wk, azoxymethane-injected rats fed corn oil had higher levels of membrane PKC lambda relative to the other treatment groups. Overall, expression of PKC lambda mRNA was not correlated with differences in the respective isozyme protein levels. Therefore, the chemopreventive effects of dietary fish oil and pectin are associated with the blockage of azoxymethane-induced alterations in colonic PKC lambda protein expression.
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PMID:Dietary fat and fiber modulate the effect of carcinogen on colonic protein kinase C lambda expression in rats. 931 48

Experimental models have several advantages in the study of colon cancer. They can be used to tightly control diet, examine putative intermediate markers, test hypotheses about mechanisms of carcinogenesis, and quantify development of tumors in a short time. Dietary issues that have been studied in animal models but are unresolved include the concept of the effects of total fat compared with energy intake, composition of the basal diet, linoleic acid requirements, and interactions of fat with other nutrients. Intermediate markers that have been probed in animal or in vitro studies include cytokinetics, aberrant crypt foci, eicosanoids and hydroxyoctadecadienoic acids, ornithine decarboxylase, tyrosine kinase, protein kinase C, and gene expression. Colon cancer is studied in animals primarily with use of chemicals that are relatively specific inducers of these tumors, but transplantable models and transgenic animals are also used. Total dietary fat is generally thought to affect colon tumorigenesis, but there does not appear to be any specific fatty acid that promotes the development of colon cancer. Several studies indicate that n-3 fatty acids from marine sources alter a variety of biological intermediates and inhibit colonic tumorigenesis; this is probably mediated via the eicosanoid pathway. Although there are undoubtedly multiple cellular changes elicited by certain fatty acids, our current knowledge of this area suggests that specific fatty acid metabolites or their targets are the likely mediators in this sequence.
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PMID:Fatty acids and colon cancer in experimental models. 939 11

The secondary bile acid deoxycholic acid is believed to be a promoter of large bowel cancer, in part by inducing colonic epithelial proliferation. The effects of deoxycholic acid on [3H]thymidine incorporation by the human colon cancer cell line HT29 and two differentiated subclones were measured and compared. The subclone HT29-C1 has features of mature absorptive cells and HT29-N2 cells secrete mucus under cholinergic control. The three cell lines were treated with deoxycholic acid (DCA) at concentrations of 0, 5, 10, 50, 100, 150, and 300 microM for 3, 6, 9, 15, 24, and 48 hr. A significant increase in proliferation was noted in HT29 cells only at 6 hr with 5 and 10 microM deoxycholic acid. Neither the subclone HT29-C1, nor HT29-N2 cells exhibited significant change in [3H]thymidine incorporation with DCA at these concentrations or time points. Higher doses of deoxycholic acid above 50 microM and duration of exposure greater than 24 hr were cytotoxic to all three cell lines. The proliferative effects of DCA in HT29 cells were not paralleled by changes in protein kinase C activity or protein kinase C isoform expression. Quantitative and qualitative differences in PKC isoform expression were not noted in the three cell lines used in this study. The proliferative effects of DCA on HT29 cells appear to be independent of the PKC signal transduction pathway.
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PMID:Differential effects of deoxycholic acid on proliferation of neoplastic and differentiated colonocytes in vitro. 939

We have developed a non-invasive method utilizing feces, containing sloughed colonocytes, as a sensitive technique for detecting diagnostic colonic biomarkers. In this study, we used the rat colon carcinogenesis model to determine if changes in fecal protein kinase C (PKC) expression have predictive value in monitoring the neoplastic process. Weanling rats were injected with saline or azoxymethane (AOM) and 36 weeks later fecal samples and mucosa were collected, poly A+ RNA isolated, and quantitative RT-PCR performed using primers to PKC betaII and zeta. Fecal PKC betaII and zeta mRNA levels were altered by the presence of a tumor, with tumor-bearing animals having a 3-fold higher (P < 0.05) PKC betaII expression as compared with animals without tumors. In addition, AOM-injection increased mucosal PKC betaII mRNA expression compared with saline controls. No effect of tumor incidence on mucosal PKC betaII expression was observed. In contrast, fecal PKC zeta expression was 2.5-fold lower (P < 0.05) in animals injected with azoxymethane versus saline. Since tumor incidence exerts a reciprocal effect on fecal PKC betaII and zeta mRNA expression, data were also expressed as the ratio between PKC betaII and zeta. The isozyme ratio was strongly related to tumor incidence, i.e. ratio for animals with tumors was 2.18 +/- 1.25, animals without tumors was 0.50 +/- 0.16, P = 0.025. We demonstrate that the expression of fecal PKC betaII and zeta may serve as a noninvasive marker for development of colon tumors. A sensitive technique for the detection of colon cancer is of importance since early diagnosis can substantially reduce mortality.
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PMID:Non-invasive detection of fecal protein kinase C betaII and zeta messenger RNA: putative biomarkers for colon cancer. 949 73

Previous studies have shown that PKC-alpha protein expression is decreased in sporadic human colon cancers, as well as in colonic tumors of rats induced by chemical carcinogens. To elucidate the potential role of PKC-alpha on several phenotypic characteristics of colon cancer cells, we have transfected cDNAs for PKC-alpha in sense or antisense orientations into CaCo-2 cells, a human colonic adenocarcinoma cell line. Transfected clones were isolated that demonstrated approximately 3-fold increases (sense transfectants) and approximately 95% decreases (antisense transfectants) in PKC-alpha expression with no significant alterations in other PKC isoforms. Transfection of CaCo-2 cells with PKC-alpha in the antisense orientation resulted in enhanced proliferation and decreased differentiation, as well as in a more aggressive transformed phenotype compared with empty vector-transfected control cells. In contrast, cells transfected with PKC-alpha cDNA in the sense orientation demonstrated decreased proliferation, enhanced differentiation, and an attenuated tumor phenotype compared with these control cells. These data show that alterations in the expression of PKC-alpha induce changes in the proliferation, differentiation, and tumorigenicity of CaCo-2 cells. Furthermore, these findings indicate that loss of PKC-alpha expression in sporadic human and chemically induced colonic cancers may confer a relative growth advantage during colonic malignant transformation.
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PMID:Decreased PKC-alpha expression increases cellular proliferation, decreases differentiation, and enhances the transformed phenotype of CaCo-2 cells. 950 Apr 74


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