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)

Macrophages can kill tumor cells by releasing high levels of nitric oxide (NO) and related reactive nitrogen species such as nitroxyl and peroxynitrite, after up-regulation of expression of the inducible nitric oxide synthase gene (iNOS). In this paper we describe two novel human cell lines that are capable of expressing high levels of iNOS under the control of analogues of either the insect hormone ecdysone or tetracycline. We have entrapped these iNOS-expressing cells within a semipermeable alginate-poly-L-lysine membrane as a means of delivery to tumor sites in a nude mouse model. These encapsulated cells can be induced to generate sustainable high concentrations NO and reactive nitrogen species at tumor sites after treatment either with ponasterone A or muristerone A or with doxycycline. Delivery of these iNOS-expressing cells to tumors formed from human ovarian cancer SKOV-3 cells results in 100% killing, whereas treatment of tumors formed from human colon cancer DLD-1 cells results in 54% killing. We show that in these iNOS-expressing cells, tumor killing is associated with concomitant up-regulation of the Fas/FasL proteins.
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PMID:Microencapsulated iNOS-expressing cells cause tumor suppression in mice. 1177 48

beta-catenin plays an important role in development and homeostasis. Deregulated beta-catenin is involved in oncogenesis. In this study, we found that beta-catenin can physically complex with NF-kappa B, resulting in a reduction of NF-kappa B DNA binding, transactivation activity, and target gene expression. Repressed NF-kappa B activity is found in human colon cancer cells in which beta-catenin is activated. Importantly, activated beta-catenin was found to inhibit the expression of NF-kappa B target genes, including Fas and TRAF1. Furthermore, a strong inverse correlation was identified between the expression levels of beta-catenin and Fas in colon and breast tumor tissues, suggesting that beta-catenin regulates NF-kappa B and its targets in vivo. Thus, beta-catenin may play an important role in oncogenesis through the crossregulation of NF-kappa B.
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PMID:beta-catenin interacts with and inhibits NF-kappa B in human colon and breast cancer. 1239 96

Type I cells have been defined to be independent of mitochondria for the induction of Fas death receptor-mediated apoptosis, whereas Type II cells are mitochondria-dependent. Knock-out studies in mice show that thymocytes are Type I and liver cells are Type II. We have previously shown that primary human hepatocytes and HCT116 human colon carcinoma cells behave like Type II cells because TRAIL-induced apoptosis can be blocked by the caspase 9 inhibitor, Z-LEHD-FMK. On the other hand, caspase 9 inhibition does not allow survival of TRAIL-treated SW480 colon cancer cells, which is predicted for Type I cells. Investigating the differences in TRAIL-induced apoptotic pathways in HCT116 and SW480 cells revealed that although FADD, BID, and procaspase 3 protein levels are higher in SW480 cells, and although procaspase 8 and FLIP processing is more efficient at the TRAIL-DISC of SW480 cells, BID, procaspase 3, XIAP, and PARP cleavages occur more rapidly in HCT116, despite the higher levels of BCL-2 and HSP70. Cytochrome c release from the mitochondria to the cytoplasm is more efficient in HCT116 cells. These results suggest BID cleavage as a possible limiting factor in the involvement of mitochondria in TRAIL-induced cell death. Thus, regulation of BID cleavage may define if a cell is mitochondria-dependent or -independent in response to TRAIL death receptor-induced apoptosis.
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PMID:Defining characteristics of Types I and II apoptotic cells in response to TRAIL. 1240 50

The pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1) is a heptahelical, G protein-coupled receptor that has been shown to be expressed by non-squamous lung cancer and breast cancer cell lines, and to be coupled to the growth of these tumors. We have previously shown that PACAP and its receptor, PAC1, are expressed in rat colonic tissue. In this study, we used polyclonal antibodies directed against the COOH terminal of PAC1, as well as fluorescently labeled PACAP, Fluor-PACAP, to demonstrate the expression of PAC1 on HCT8 human colonic tumor cells, using FACS analysis and confocal laser scanning microscopy. Similarly, anti-PACAP polyclonal antibodies were used to confirm the expression of PACAP hormone by this cell line. We then investigated the signal transduction properties of PAC1 in these tumor cells. PACAP-38 elevated intracellular cAMP levels in a dose-dependent manner, with a half-maximal (EC(50)) stimulation of approximately 3 nM. In addition, PACAP-38 stimulation caused an increase in cytosolic Ca(2+) concentration [Ca(2+)](i), which was partially inhibited by the PACAP antagonist, PACAP-(6-38). Finally, we studied the potential role of PACAP upon the growth of these tumor cells. We found that PACAP-38, but not VIP, increased the number of viable HCT8 cells, as measured by MTT activity. We also demonstrated that HCT8 cells expressed the Fas receptor (Fas-R/CD95), which was subsequently down-regulated upon activation with PACAP-38, further suggesting a possible role for PACAP in the growth and survival of these tumor cells. These data indicate that HCT8 human colon tumor cells express PAC1 and produce PACAP hormone. Furthermore, PAC1 activation is coupled to adenylate cyclase, increase cytosolic [Ca(2+)](i), and cellular proliferation. Therefore, PACAP is capable of increasing the number of viable cells and regulating Fas-R expression in a human colonic cancer cell line, suggesting that PACAP might play a role in the regulation of colon cancer growth and modulation of T lymphocyte anti-tumoral response via the Fas-R/Fas-L apoptotic pathway.
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PMID:PAC1 and PACAP expression, signaling, and effect on the growth of HCT8, human colonic tumor cells. 1240 23

Boswellic acids are the effective components of gum resin of Boswellia serrata, which has anti-inflammatory properties. Recent studies on brain tumors and leukemic cells indicate that boswellic acids may have antiproliferative and apoptotic effects with the mechanisms being not studied in detail. We studied their antiproliferative and apoptotic effects on colon cancer cells and the pathway leading to apoptosis. HT-29 cells were treated with beta-boswellic acid (BA), keto-beta-boswellic acid (K-BA) and acetyl-keto-beta-boswellic acid (AK-BA), respectively. Apoptosis was determined by flow cytometry, by cytoplasmic DNA-histone complex and the activity of caspase-3. The cleavage of poly-(ADP-ribose)-polymerase (PARP) and expression of Fas were examined by western blot. Specific caspase inhibitors, polyclonal Fas antibody, and antagonistic Fas antibody ZB4 were employed to elucidate apoptotic pathways. DNA synthesis and cell viability were examined. Both K-BA and AK-BA increased cytoplasmic DNA-histone complex dose-dependently and increased pre-G(1) peak in flow cytometer analysis, with the effects of AK-BA being stronger than K-BA. BA only increased the formation of DNA-histone complex at a high concentration. K-BA and AK-BA increased caspase-8, caspase-9 and caspase-3 activities accompanied by cleavage of PARP. The effects of AK-BA on formation of cytoplasmic DNA histone and on caspase-3 activation were 3.7- and 3.4-fold, respectively, more effective than those induced by camptothecin. The apoptosis induced by AK-BA was inhibited completely by caspase-3 or caspase-8 inhibitor and partially by caspase-9 inhibitor. ZB4 blocked exogenous Fas ligand-induced apoptosis, but had no effect on AK-BA-induced apoptosis. AK-BA had no significant effect on expression of Fas. Apart from apoptotic effect, these acids also inhibited [(3)H]thymidine incorporation and cell viability to different extent. In conclusion, boswellic acids, particularly AK-BA and K-BA have antiproliferative and apoptotic effects in human HT-29 cells. The apoptotic effect is mediated via a pathway dependent on caspase-8 activation but independent of Fas/FasL interaction.
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PMID:Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells. 1250 32

Colon cancer cells are resistant to FasR-mediated apoptosis, which contributes to their evasion from immune attack by CTLs and NK cells. FasR refractoriness of the malignancies was reported to result from loss of Fas receptors and overepression of Fas-associated phosphatase-1 (FAP-1). Therefore, we investigated the effects of recombinant IL-2 on FasR and FAP-1 expression of colon cancer cells, and its influence on the sensitivity of colon cancer cells to FasR-mediated apoptosis. Colon cancer cell lines SW480, HT-29 and CaCo2 were incubated with IL-2 for different periods of time. Sensitivity of the cells to FasR-mediated apoptosis was assessed by measuring their apoptosis after treated with agonistic anti-FasR MAb CH-11. Additionally, Fas receptor levels were examined by immunofluorescence and mRNA expression of FasR and FAP-1 was investigated by RT-PCR: IL-2 incubation increased CH11-induced apoptosis in all colon cancer cell lines in a time-dependent manner. In parallel, IL-2 up-regulated Fas receptor expression on HT29 and CaCo2 cells at both protein and mRNA levels, which were low before treatment, while it served to maintain high expression of FasR on SW480 cells. Additionally, IL-2 down-regulated FAP-1 mRNA expression on SW480 and CaCo2 cells, which was high before treatment. However, low expression of FAP1 on HT-29 cells remained stable after IL-2 treatment. Thus, IL-2 enhances susceptibility of colon cancer cells to FasR-mediated apoptosis by up-regulating Fas receptor levels and by down-regulating FAP-1 expression, which accounts for its therapeutic effects on abolishing immune evasion in colon cancer cells.
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PMID:Interleukin-2 enhances susceptibility of colon cancer cells to FasR mediated apoptosis by up-regulating Fas receptor level and down-regulating FAP-1 expression. 1265

Cytokines such as Fas-ligand (Fas-L) and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) can induce human colon cancer cell apoptosis through engagement of their death domain receptors. All the cancer cells are not sensitive to these cytokines. We have shown recently that low doses of cytotoxic drugs could restore TRAIL-induced cell death in resistant colon cancer cell lines. The present work further explores the death pathway triggered by the cytotoxic drug/TRAIL combination in HT-29 colon cancer cells (www.alexis-corp.com). Clinically relevant concentrations of cisplatin, doxorubicin and 5-fluorouracil synergize with TRAIL to trigger HT-29 cell death. Activation of this pathway leads to apoptosis that involves both caspases and the mitochondria. An increased recruitment of Fas-associated death domain (FADD) and procaspase-8 to the TRAIL-induced death-inducing signaling complex (DISC) was shown in cells exposed to anticancer drugs. Following caspase-8 activation at the DISC level, the mitochondria-dependent death pathway is activated, as demonstrated by the cleavage of Bid, the dissipation of DeltaPsi(m), the release of mitochondrial proteins in the cytosol and the inhibitory effect of Bcl-2 expression. Importantly, besides mitochondrial potentiation, we show here that cytotoxic drugs sensitize HT-29 colon cancer cells to TRAIL-induced cell death by enhancing FADD and procaspase-8 recruitment to the DISC, a novel mechanism whose efficacy could depend partly on Bcl-2 expression level.
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PMID:Chemotherapy enhances TNF-related apoptosis-inducing ligand DISC assembly in HT29 human colon cancer cells. 1266 Aug 16

Thymidylate synthase (TS) is an important target for chemotherapy and increased levels are associated with resistance to colorectal cancer chemotherapy. TS can be inhibited by 5-fluorouracil (5-FU) and antifolates, ultimately resulting in apoptosis. We aimed to clarify whether activation of caspases and Fas signalling are crucial for the onset of apoptosis after specific inhibition of TS and whether p53 plays a role in activation of these downstream processes. For this purpose, wild-type (wt) and mutant (mt) p53 colon cancer cell lines, Lovo and WiDr, respectively, transfected with mt- and wt-p53, were treated with the specific TS inhibitor, AG337. Treatment with 10xIC(50) values of AG337 for 48 h resulted in S phase arrest in all Lovo and WiDr cells (up to 50% of cells being in S phase), irrespective of their p53 status. After 72 h, the induction of apoptosis was most pronounced in the AG337-sensitive cells. Approximately 30% apoptosis was detected in all of the WiDr cells, 20% in Lovo li (non-functional p53), 12-14% in Lovo 92 and B2 (wt p53) and only 7% in Lovo 175x2 cells (mt p53 transfected). The induction of apoptosis in Lovo cells, as determined using the classical sub-G1 peak after propidium iodide (PI) staining, was associated with an increase in the expression of Fas receptor. In addition, synergistic increases in apoptosis from approximately 10 to 35% after 48 h could be detected after simultaneous treatment of AG337 and the Fas activator antibody, CH11. Only additive effects were measurable in WiDr cells, without an increase in Fas receptor expression. Surprisingly, the Fas inhibitor, ZB4, could not decrease the amount of cell death in both cell lines after AG337 treatment. In contrast, simultaneous exposure of Lovo and WiDr cells to AG337 and inhibitors of caspases 8, 9 and 3 caused a decrease in the number of apoptotic cells compared with AG337 exposure alone. Inhibition of apoptosis by approximately 10-80% in Lovo and approximately 70-80% in WiDr cells could be detected. In conclusion, these results indicate that apoptosis induced after specific inhibition of TS is mediated via the caspases, but without clear involvement of Fas signalling. The status of p53 did not affect the onset of apoptosis by these caspases.
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PMID:Thymidylate synthase inhibition triggers apoptosis via caspases-8 and -9 in both wild-type and mutant p53 colon cancer cell lines. 1276 22

The Fas/Fas ligand (FasL) system is one apoptotic pathway through which malignant tumors can evade immune surveillance. While FasL is expressed in malignant tumors, Fas is conversely downregulated to escape host immune attack, resulting in tumor invasion. The aim of the current study was to find out further clinicopathological significance of FasL expression in carcinoma of the colon and rectum. FasL expression was investigated using immunohistochemical staining in 143 consecutive patients with primary colorectal carcinomas. Seventy-nine carcinomas (55.2%) expressed FasL. The incidence of lymph node and distant metastases in carcinomas expressing FasL was significantly higher than in carcinomas that did not express FasL (p = 0.031 and p = 0.0003, respectively). Although univariate analysis showed that survival in patients with carcinomas expressing FasL was significantly poorer than that in patients with carcinomas without FasL expression (p = 0.001), only Dukes' stage was an independent prognosticator by multivariate analysis. FasL expression was found to be correlated with lymph node involvement and distant metastases in colorectal carcinoma.
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PMID:Fas ligand expression is correlated with metastasis in colorectal carcinoma. 1283 86

Resveratrol, a polyphenol found in grape skin and various other food products, may function as a cancer chemopreventive agent for colon and other malignant tumors and possesses a chemotherapeutic potential through its ability to trigger apoptosis in tumor cells. The present study analyses the molecular mechanisms of resveratrol-induced apoptosis in colon cancer cells, with special attention to the role of the death receptor Fas in this pathway. We show that, in the 10-100 microm range of concentrations, resveratrol activates various caspases and triggers apoptosis in SW480 human colon cancer cells. Caspase activation is associated with accumulation of the pro-apoptotic proteins Bax and Bak that undergo conformational changes and relocalization to the mitochondria. Resveratrol does not modulate the expression of Fas and Fas-ligand (FasL) at the surface of cancer cells, and inhibition of the Fas/FasL interaction does not influence the apoptotic response to the molecule. Resveratrol induces the clustering of Fas and its redistribution in cholesterol and sphingolipid-rich fractions of SW480 cells, together with FADD and procaspase-8. This redistribution is associated with the formation of a death-inducing signaling complex (DISC). Transient transfection of either a dominant-negative mutant of FADD, E8, or MC159 viral proteins that interfere with the DISC function, decreases the apoptotic response of SW480 cells to resveratrol and partially prevents resveratrol-induced Bax and Bak conformational changes. Altogether, these results indicate that the ability of resveratrol to induce the redistribution of Fas receptor in membrane rafts may contribute to the molecule's ability to trigger apoptosis in colon cancer cells.
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PMID:Resveratrol-induced apoptosis is associated with Fas redistribution in the rafts and the formation of a death-inducing signaling complex in colon cancer cells. 1290 49


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