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)

We previously designed and characterized an in vitro model of the intrinsic drug resistance of human colon cancer. The human colonic epithelium is chronically exposed to endogenous protein kinase C (PKC) stimulatory factors, and our model demonstrated that activation of PKC induces resistance to multiple anticancer drugs in the metastatic human colon cancer cell line KM12L4a. PKC is an isozyme family with ten members, eight of which are phorbol ester-responsive. In this report, we show that thymeleatoxin (Tx), a daphnane tumor promoter that selectively activates the phorbol ester-responsive isozymes cPKC-alpha, -beta 1, -beta 2, and -gamma, was just as effective in inducing drug resistance in KM12L4a cells as phorbol dibutyrate, a potent activator of all phorbol ester-responsive PKC isozymes. The induction of resistance by Tx was associated with a reduction in cytotoxic drug accumulation in KM12L4a cells. We demonstrated by immunoblot analysis and hydroxylapatite chromatography that KM12L4a cells express active cPKC-alpha but not cPKC-beta 1, -beta 2, or gamma. Our results provide strong evidence that phorbol-ester activation of cPKC-alpha is sufficient for the induction of resistance observed in KM12L4a cells. The possibility that endogenous PKC activators may induce intrinsic drug resistance in clinical colon cancer by an analogous mechanism is strongly suggested by our detection of active cPKC-alpha in surgical specimens of human colon carcinomas.
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PMID:Evidence that protein kinase C-alpha activation is a critical event in phorbol ester-induced multiple drug resistance in human colon cancer cells. 805 34

The plasminogen activator urokinase promotes tumor invasion by converting plasminogen into plasmin, which degrades several extracellular matrix components. Urokinase can bind to a specific cell surface receptor, which leads to accelerated plasmin production. While there is good evidence indicating a role for this binding site in tumor invasion/metastasis, there is little information concerning the regulation of urokinase receptor expression in invasive cancer. To address this question a series of colon cancer cell lines, which demonstrate either a high or low ability to invade an extracellular matrix-coated porous filter, was characterized for receptor expression at the transcriptional and post-transcriptional levels. The invasive cell lines possessed 10-fold more receptors than their non-invasive counterparts as shown by cross-linking experiments and by Western blotting. Northern blotting indicated that this disparity in receptor number could be largely accounted for by a different amount of steady-state mRNA encoding the binding site. However, neither gene amplification nor enhanced mRNA stability could account for the augmented receptor protein observed for the invasive colon cancer cell types. In contrast, nuclear run-on experiments with representative cell lines revealed that the 10-fold difference in receptor display between the invasive-competent and invasive-deficient cells could be largely accounted for by differences in transcription rates. Transcription of the u-PAR gene in the receptor-deficient GEO cells, but not in the receptor-rich RKO cells, could be augmented by protein kinase C stimulation. These findings provide a clear rationale for studies to determine if the urokinase receptor promoter in invasive colon cancer is activated in cis or in trans.
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PMID:Transcriptional activation of the urokinase receptor gene in invasive colon cancer. 807 48

We have studied the PKC isoforms present in HT-29 M6 colon cancer cells, the differentiation of which to mucus-secreting cells is blocked by TPA. In addition to a major 72 kDa band, a 77 kDa PKC isoform was recognized by two different antibodies raised against a C-terminus-specific peptide for the TPA-insensitive isoform, PKC zeta. By different criteria (association to the membrane, down-regulation, PKC activity in immunoprecipitates) we conclude that, contrary to the 72 kDa band, the 77 kDa band corresponds to a Ca(2+)- and TPA-sensitive PKC. These results suggest that antipeptide antibodies directed against the C-terminus of PKC zeta react in human cells with a member of the conventional PKC subfamily besides PKC zeta. Therefore, the data indicating that PKC zeta is sensitive to different agents in various cell lines should be carefully re-evaluated.
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PMID:Antipeptide antibodies directed against the C-terminus of protein kinase C zeta (PKC zeta) react with a Ca(2+)- and TPA-sensitive PKC in HT-29 human intestinal epithelial cells. 818 76

The high affinity receptor of phorbol-ester and related tumor promoters is the isozyme family protein kinase C (PKC). Activation of PKC by the phorbol esters is a pivotal event in phorbol ester-mediated tumor promotion. PKC activation is also implicated in tumor promotion of colonic epithelial cells by endogenous and dietary factors such as bile acids, free fatty acids, and diacylglycerols, suggesting that suppression of the inappropriate activation of colonic epithelial PKC by these factors could be an effective strategy of chemoprevention. Phorbol-ester tumor promoters induce pleiotropic resistance against anti-cancer drugs in cultured human colon cancer cells. By characterizing PKC isozyme expression in the cells and the induction of resistance by isozyme-selective PKC activators, we have obtained evidence that the induction of resistance is triggered by phorbol-ester activation of cPKC-alpha. We have also found that cPKC-alpha is expressed abundantly in surgical specimens of human colon cancer, indicating that cPKC-alpha-mediated drug resistance may contribute to the intrinsic drug resistance of clinical colon cancer. The intrinsic resistance of human colon cancer to multiple anticancer drugs precludes effective therapy of disseminated disease with available chemotherapeutic regimens. The development of reversal agents of intrinsic drug resistance that function by selective inhibition of cPKC-alpha might allow successful management of the disease with standard cytotoxic chemotherapeutic regimens.
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PMID:The tumor promoter receptor protein kinase C: a novel target for chemoprevention and therapy of human colon cancer. 853 10

Deaths from colon cancer number over 60,000 each year in the United States. Because early detection results in a high cure rate, development of noninvasive techniques for detection of colon cancer has received much interest. The ability to detect early changes in colonocyte genes and gene expression would provide valuable information. We have shown previously that alterations in protein kinase C (PKC) isoform expression are associated with changes in colonic cell proliferation, a key intermediate marker for the prediction of tumorigenesis. Here, we describe a method for the quantitative detection of mRNAs for select PKC isoforms isolated from rat feces containing exfoliated colonocytes. After total RNA extraction from fresh fecal material, polyadenylated RNA was selectively purified and quantitated with slot blotting and hybridization to oligodeoxythymidylic acid. Fecal polyadenylated RNA was used for semiquantitative (mimic) RT-PCR to quantitate PKC isoform mRNA expression. We detected mRNA for PKC-alpha, PKC-delta, PKC-epsilon, and PKC-sigma, but not for PKC-beta or PKC-gamma, which is consistent with the profile of isoforms detected previously in scraped colonic mucosa using immunoblot analysis. This noninvasive method, utilizing feces containing exfoliated colonocytes, is a sensitive noninvasive technique for quantitating luminal mRNAs. This provides a means to monitor gene expression of colonic epithelial cells, which may have predictive value in monitoring the neoplastic process.
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PMID:Noninvasive detection of putative biomarkers for colon cancer using fecal messenger RNA. 854 31

In a prior study, we have shown that stable transfection of expression plasmids for protein kinases C beta 1 (PKC beta 1) or PKC beta 2 into differentiated colon cancer cells led to elevated levels of PKC beta 1 or PKC beta 2 protein and PKC beta kinase activities in the transfectants, without altering PKC alpha levels. PKC gamma is not found in these cells, so the major modulation was in PKC beta. PKC beta transfectant cells exhibited blocked differentiation, increased growth rate in athymic mice, and restoration of the basic fibroblast growth factor response pathway. In this study, we have extended the analysis of these PKC beta transfectants to the mitogen-activated protein kinase ERK3. Analysis of cell lysates on the mitogen-activated protein kinase substrate myelin basic protein by in gel kinase assay showed increased activity at 63 kDa, the size of ERK3, in each of two PKC beta 1 and each of two PKC beta 2 transfectants compared with the vector control transfectant. ERK3 was expressed at equal abundance in PKC beta 1, PKC beta 2, and control transfectant cells as demonstrated by Western blotting and by immunoprecipitation with anti-ERK3 monoclonal antibody. However, a > 10-fold increase in ERK3 activity in each PKC beta transfectant was shown by immunoprecipitation with anti-ERK3 monoclonal antibody followed by either immune complex kinase assay or by in gel kinase assay. Thus, while overexpression of transfected PKC beta does not lead to overexpression of ERK3, it does lead to constitutive activation of ERK3. A causal link between PKC beta overexpression and ERK3 activation was established because 12-O-tetradecanoylphorbol-13-acetate treatment down-regulated both PKC and ERK3 activities in both PKC beta 1 transfectants. ERK3 activity was found in nuclear and membrane fractions in each PKC beta transfectant, in contrast to controls, perhaps accounting for constitutive activation of ERK3 in cells with elevated levels of PKC beta 1 or PKC beta 2.
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PMID:Increased expression of protein kinase C beta activates ERK3. 862 98

Butyrate is a potentially selective therapeutic agent for many adenocarcinomas. Butyrate causes reversible growth arrest as well as some death of VACO 5 colon cancer cells. Combined treatment with butyrate and the phorbol ester TPA leads instead only to cell death, while TPA causes little death on its own. Cells dying during treatment with TPA and butyrate, as well as those dying in the presence of butyrate alone, exhibit features typical of apoptosis, including detachment, shrinkage and internucleosomal DNA cleavage. Pre-treating VACO 5 cell cultures with TPA for as little as 6 hr prior to butyrate addition led to a markedly diminished enhancement of butyrate-induced apoptosis. Treatment with a distinct PKC activator, bryostatin 1, was ineffective in enhancing butyrate-induced death and, furthermore, counteracted the death-enhancing actions of TPA. Such antagonism was apparent when bryostatin was added after 12 hr of TPA/butyrate treatment but was much less effective thereafter. The duration of TPA/butyrate treatment required for depressing cell survival by >95% was thereby estimated to be 24 hr. Other colon cancer cell lines were examined for the extent of cell death following treatment with TPA/butyrate. In each of these lines, butyrate inhibited cell replication in a reversible manner, similar to that seen in VACO 5. However, the combination of butyrate and TPA led to high levels of cell death in only a subset of these lines. TPA/butyrate-treated cultures of COLO 201 exhibited extensive apoptosis, similar in timing and magnitude to the response by VACO 5, whereas HCT 116 was reversibly growth-arrested. Our findings indicate that the PKC system plays a critical role in maintaining cell survival during butyrate-induced growth arrest.
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PMID:Phorbol ester augments butyrate-induced apoptosis of colon cancer cells. 878 64

Elevation in intracellular Ca2+ acting via protein kinase C (PKC) is shown to regulate tight junction resistance in T84 cells, a human colon cancer line and a model Cl- secretory epithelial cell. The Ca2+ ionophore A23187, which was used to increase the intracellular Ca2+ concentration, caused a decrease in tight junction resistance in a concentration- and time-dependent manner. Dual Na+/mannitol serosal-to-mucosal flux analysis performed across the T84 monolayers treated with 2 microM A23187 revealed that A23187 increased both fluxes and that in the presence of ionophore there was a linear relationship between the Na+ and mannitol fluxes with a slope of 56.4, indicating that the decrease in transepithelial resistance was due to a decrease in tight junction resistance. Whereas there was no effect of 0.1 microM A23187, 1 or 2 microM produced a 55% decrease in baseline resistance in 1 hr and 10 microM decreased resistance more than 80%. The A23187-induced decrease in tight junction resistance was partially reversible by washing 3 times with a Ringer's-HCO3 solution containing 1% BSA. The A23187 effect on resistance was dependent on intracellular Ca2+; loading the T84 cells with the intracellular Ca2+ chelator BAPTA significantly reduced the decrease in tight junction resistance caused by A23187. This intracellular Ca2+ effect was mediated by protein kinase C and not calmodulin. While the protein kinase C antagonist H-7 totally prevented the action of A23187 on tight junction resistance, the Ca2+/calmodulin inhibitor W13 did not have any effect. Sphingosine, another inhibitor of PKC, partially reduced the A23187-induced decline in tight junction resistance. The PKC agonist PMA mimicked the A23187 effect on resistance, although the effect was delayed up to 1 hr after exposure. In addition, however, PMA also caused an earlier increase in resistance, indicating it had an additional effect in addition to mimicking the effect of elevating Ca2+. The effects of a phospholipase inhibitor (mepacrine) and of inhibitors of arachidonic acid metabolism (indomethacin for the cyclooxygenase pathway, NDGA for the lipoxygenase pathway, and SKF 525A for the epoxygenase pathway) on the A23187 action were also examined. None of these agents altered the A23187-induced decrease in resistance. Monolayers exposed to 2 microM A23187 for 1 hr were stained with fluorescein conjugated phalloidin, revealing that neighboring cells did not part one from another and that A23187 did not have a detectable effect on distribution of F-actin in the perijunctional actomyosin ring. The results indicate that elevation in intracellular Ca2+ decreases tight junction resistance in the T84 monolayer, acting through protein kinase C by a mechanism which does not involve visible changes in the perijunctional actomyosin ring.
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PMID:Regulation of tight junction resistance in T84 monolayers by elevation in intracellular Ca2+: a protein kinase C effect. 882 30

Curcumin, which is a widely used dietary pigment and spice, has been demonstrated to be an effective inhibitor of tumor promotion in mouse skin carcinogenesis. We report that curcumin induces cell shrinkage, chromatin condensation, and DNA fragmentation, characteristics of apoptosis, in immortalized mouse embryo fibroblast NIH 3T3 erb B2 oncogene-transformed NIH 3T3, mouse sarcoma S180, human colon cancer cell HT-29, human kidney cancer cell 293, and human hepatocellular carcinoma Hep G2 cells, but not in primary culture of mouse embryonic fibroblast C3H 10T1/2, rat embryonic fibroblast, and human foreskin fibroblast cells in a concentration- and time-dependent manner. Many cellular and biochemical effects of curcumin in mouse fibroblast cells have been reported, such as inhibition of protein kinase C (PKC) activity induced by phorbol 12-myristate 13-acetate treatment, inhibition of tyrosine protein kinase activity, and inhibition of arachidonic acid (AA) metabolism. Treatment of NIH 3T3 cells with the PKC inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin A, and the AA metabolism inhibitor quinacrine induces apoptotic cell death. These results suggest that, in some immortalized and transformed cells, blocking the cellular signal transduction might trigger the induction of apoptosis.
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PMID:Curcumin induces apoptosis in immortalized NIH 3T3 and malignant cancer cell lines. 884 27

Considerable evidence suggests that dietary differences between populations account for a significant proportion of the variation in cancer occurrence in different parts of the world. A major problem has been identifying the particular dietary components which predispose or protect individuals against cancer. For example, the high rates of breast and colon cancer in the United States have been associated with numerous dietary patterns including high fat, high dietary energy, and low fruit and vegetable intakes. Our laboratories have attempted to identify mechanisms whereby diet may modify cancer and it is anticipated that future studies will determine which of these potential mechanisms may be relevant in humans. A promising lead in understanding the mechanism of high dietary fat/high dietary energy promotion of cancer was the impact of these diets on cellular protein kinase C (PKC). PKC is important in cellular signaling events which are critical to tumor promotion. Our studies demonstrated increased PKC activity and/or protein expression observed in epidermis and pancreatic epithelial cells of rodents fed high fat/energy diets. The inverse association between cancer at a number of sites and fruit and vegetable intake may be due to both micronutrient and non-nutrient components of fruits and vegetables. We have studied the prevention of skin tumor promotion by apigenin, a plant flavonoid. Apigenin may block several points in the process of tumor promotion, including inhibiting kinases, reducing transcription factors and regulating cell cycle. The complexity of our diets and the multitude of potential dietary effects which may be important in cancer development make this a fertile area for future study.
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PMID:Diet intervention for modifying cancer risk. 889 92


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