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 Fas (CD95, APO-1) receptor is a transmembrane cell surface receptor that mediates apoptosis in many cell types when bound by the Fas ligand or cross-linked by agonistic anti-Fas antibodies. Fas activation engages a potent and rapid signaling mechanism in a variety of cell types. In the present study, we have investigated the effects of Fas receptor activation on CYP3A4 expression in human colon carcinoma HT-29 cells. The intracellular ceramide levels were significantly enhanced by the treatment with the anti-Fas antibodies and both CYP3A4 protein and mRNA expression was suppressed by Fas activation in a dose-dependent manner. Immunoblot analyses showed that the expression of iNOS protein was significantly stimulated by an anti-Fas antibody treatment in HT-29 cells. Fas receptor activation also increased the generation of reactive oxygen species, and N-acetylcysteine, a well-known antioxidant, could block Fas-mediated iNOS induction. These results show that the Fas receptor-mediated signaling pathways modulate CYP3A4 expression in human colon cancer cells. Overall, iNOS induction and P450 3A4 suppression by Fas activation may cause toxic cellular damage in gastrointestinal tissues.
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PMID:Activation of Fas receptor modulates cytochrome P450 3A4 expression in human colon carcinoma cells. 1461 69

Cancer cells are thought to possess mechanisms for evading the host's immune surveillance system. Survivin, a member of the inhibitor-of-apoptosis family overexpressed by cancer cells, inhibits Fas-mediated apoptosis induced by immune cells. In addition, cancer cells express Fas ligand (FasL) on their surfaces as a counterattack against immune cells. Mechanisms by which cancer cells express FasL, including involvement of survivin, are unclear. In the present study, we demonstrated that survivin up-regulated FasL expression and investigated how this might occur. Quantitative immunostaining showed correlation between survivin and FasL protein expression in colon cancer tissues (r=0.79). FasL expression was up-regulated in LS180 colon cancer cells transfected with the survivin gene. Transfectants showed increased cytotoxicity against a Fas-sensitive human T leukemia cell line, Jurkat. In contrast, FasL expression was down-regulated in SW480 cells transfected with a small inhibitory RNA to prevent survivin expression. Survivin gene transfectants showed increased DNA binding of transcription factor specificity protein 1 (Sp1) to the FasL promoter, and up-regulation of Sp1 phosphorylation at serine and threonine residues; the total amount of Sp1 was unchanged. Thus, survivin enables cancer cells not only to suppress immune cell attack by inhibiting Fas-mediated apoptotic signaling, but to attack immune cells by induction of FasL.
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PMID:Survivin enhances Fas ligand expression via up-regulation of specificity protein 1-mediated gene transcription in colon cancer cells. 1500

Various human colon cancer cell lines tested in vitro differed significantly in susceptibility to growth inhibition of recombinant human interferon-beta (rHuIFN-beta). Two p53-mutant lines, COH and CC-M2, derived from high-grade colon adenocarcinoma, showed signs of apoptosis after treatment with 250 IU/ml of HuIFN- beta in the culture medium. The similarly p53-mutated HT-29 line from a grade I adenocarcinoma showed no apoptosis, however, and only cell cycle G1/G0 or S phase retardation with 1000 IU/ml HuIFN-beta. After HuIFN-beta exposure, COH and CC-M2 cells showed increased levels of Fas and FasL proteins, alteration of mitochondrial membrane potential, and activation of caspase-9, caspase-8, and caspase-3 in a time-dependent manner. Treatment of COH and CC-M2 cells with anti-FasL antibodies or rFas/Fc fusion protein, however, could not prevent the apoptosis induced by HuIFN-beta. In contrast, cell-permeable specific inhibitors of the three caspases could inhibit the DNA fragmentation and cell death but not the mitochondrial membrane potential changes. Treatment with mitochondria-stabilizing reagents could significantly abrogate the apoptosis and caspase activation induced by HuIFN-beta. These results suggest that in COH and CC-M2 colon cancer cell lines, HuIFN-beta induces apoptosis mainly through mitochondrial membrane alteration and subsequent activation of the caspase cascade pathway, but not by the Fas/FasL interaction or the p53-dependent apoptotic mechanism.
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PMID:IFN-beta induces caspase-mediated apoptosis by disrupting mitochondria in human advanced stage colon cancer cell lines. 1514 69

We have shown previously that the death receptor CD95 could contribute to anticancer drug-induced apoptosis of colon cancer cells. In addition, anticancer drugs cooperate with CD95 cognate ligand or agonistic antibodies to trigger cancer cell apoptosis. In the present study, we show that the anticancer drug cisplatin induces clustering of CD95 at the surface of the human colon cancer cell line HT29, an event inhibited by the inhibitor of acid sphingomyelinase (aSMase) imipramine. The cholesterol sequestering agent nystatin also prevents cisplatin-induced CD95 clustering and decreases HT29 cell sensitivity to cisplatin-induced apoptosis and the synergy between cisplatin and anti-CD95 agonistic antibodies. CD95, together with the adaptor molecule Fas-associated death domain and procaspase-8, is redistributed into cholesterol- and sphingolipid-enriched cell fractions after cisplatin treatment, suggesting plasma membrane raft involvement. Interestingly, nystatin prevents the translocation of the aSMase to the extracellular surface of plasma membrane and the production of ceramide, suggesting that these early events require raft integrity. In addition, nystatin prevents cisplatin-induced transient increase in plasma membrane fluidity that could be required for CD95 translocation. Together, these results demonstrate that cisplatin activates aSMase and induces ceramide production, which triggers the redistribution of CD95 into the plasma membrane rafts. Such redistribution contributes to cell death and sensitizes tumor cells to CD95-mediated apoptosis.
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PMID:Cisplatin-induced CD95 redistribution into membrane lipid rafts of HT29 human colon cancer cells. 1515 Jan 17

Fas (CD95/Apo-1) is a member of the tumor necrosis factor receptor family. Receptor binding results in activation of caspase 8, leading to activation of proapoptotic downstream molecules. We found that expression of Fas was up-regulated >10-fold in MCF-7 breast and HCT116 and RKO colon cancer cell lines after treatment with IC(60) doses of 5-fluorouracil (5-FU) and raltitrexed (RTX). Combined treatment with the agonistic Fas antibody CH-11 and either 5-FU or RTX resulted in a highly synergistic induction of apoptosis in these cell lines. Similar results were obtained for another antifolate, Alimta. Induction of thymidylate synthase expression inhibited Fas induction in response to RTX and Alimta, but not in response to 5-FU. Furthermore, thymidylate synthase induction abrogated the synergy between CH-11 and both antifolates but had no effect on the synergistic interaction between 5-FU and CH-11. Inactivation of p53 in MCF-7 and HCT116 cell lines blocked 5-FU- and antifolate-mediated up-regulation of Fas. Furthermore, Fas was not up-regulated in response to 5-FU or antifolates in the p53-mutant H630 colon cancer cell line. Lack of Fas up-regulation in the p53-null and -mutant lines abolished the synergistic interaction between 5-FU and CH-11. Interestingly, synergy was still observed between the antifolates and CH-11 in the p53-null HCT116 and p53-mutant H630 cell lines, although this was significantly reduced compared with the p53 wild-type cell lines. Our results indicate that Fas is an important mediator of apoptosis in response to both 5-FU and antifolates.
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PMID:The roles of thymidylate synthase and p53 in regulating Fas-mediated apoptosis in response to antimetabolites. 1516 16

Colon cancer is the third most common cancer globally. The risk of developing colon cancer is influenced by a number of factors that include age and diet, but is primarily a genetic disease, resulting from oncogene over-expression and tumour suppressor gene inactivation. The induction and progression of the disease is briefly outlined, as are the cellular changes that occur in its progression. While colon cancer is uniformly amenable to surgery if detected at the early stages, advanced carcinomas are usually lethal, with metastases to the liver being the most common cause of death. Oncogenes and genetic mutations that occur in colon cancer are featured. The molecules and signals that act to eradicate or initiate the apoptosis cascade in cancer cells, are elucidated, and these include caspases, Fas, Bax, Bid, APC, antisense hTERT, PUMA, 15-LOX-1, ceramide, butyrate, tributyrin and PPARgamma, whereas the molecules which promote colon cancer cell survival are p53 mutants, Bcl-2, Neu3 and COX-2. Cancer therapies aimed at controlling colon cancer are reviewed briefly.
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PMID:Colon cancer: genomics and apoptotic events. 1525 76

Tumor resistance to current drugs prevents curative treatment of human colon cancer. A pressing need for effective, tumor-specific chemotherapies exists. The non-receptor-tyrosine kinase c-Src is overexpressed in >70% of human colon cancers and represents a tractable drug target. KM12L4A human metastatic colon cancer cells were stably transfected with two distinct kinase-defective mutants of c-src. Their response to oxaliplatin, to SN38, the active metabolite of irinotecan (drugs active in colon cancer), and to activation of the death receptor Fas was compared with vector control cells in terms of cell cycle arrest and apoptosis. Both kinase-defective forms of c-Src co-sensitized cells to apoptosis induced by oxaliplatin and Fas activation but not by SN38. Cells harboring kinase-defective forms of c-Src carrying function blocking point mutations in SH3 or SH2 domains were similarly sensitive to oxaliplatin, suggesting that reduction in kinase activity and not a Src SH2-SH3 scaffold function was responsible for the observed altered sensitivity. Oxaliplatin-induced apoptosis, potentiated by kinase-defective c-Src mutants, was dependent on activation of caspase 8 and associated with Bid cleavage. Each of the stable cell lines in which kinase-defective mutants of c-Src were expressed had reduced levels of Bcl-x(L.) However, inhibition of c-Src kinase activity by PP2 in vector control cells did not alter the oxaliplatin response over 72 h nor did it reduce Bcl-x(L) levels. The data suggest that longer term suppression of Src kinase activity may be required to lower Bcl-x(L) levels and sensitize colon cancer cells to oxaliplatin-induced apoptosis.
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PMID:Expression of kinase-defective mutants of c-Src in human metastatic colon cancer cells decreases Bcl-xL and increases oxaliplatin- and Fas-induced apoptosis. 1532 64

The natural phytoalexin resveratrol (3, 5, 4'-trihydroxystilbene) exhibits both chemopreventive and antitumor activities through a variety of mechanisms. We have shown previously that resveratrol-induced apoptosis of a human colon cancer cell line involved the redistribution of CD95 (Fas/Apo-1) into lipid rafts. Here, we show that, in colon cancer cells that resist to resveratrol-induced apoptosis, the polyphenol also induces a redistribution of death receptors into lipid rafts. This effect sensitizes these tumor cells to death receptor-mediated apoptosis. In resveratrol-treated cells, tumor necrosis factor (TNF), anti-CD95 antibodies and TNF-related apoptosis-inducing ligand (TRAIL) activate a caspase-dependent death pathway that escapes Bcl-2-mediated inhibition. Resveratrol does not enhance the number of death receptors at the surface of tumor cells but induces their redistribution into lipid rafts and facilitates the caspase cascade activation in response to death receptor stimulation. The cholesterol sequestering agent nystatin prevents resveratrol-induced death receptor redistribution and cell sensitization to death receptor stimulation. Thus, whatever its ability to induce apoptosis in a tumor cell, resveratrol induces redistribution of death receptors into lipid rafts. This redistribution sensitizes the cells to death receptor stimulation. Such a sensitizing effect may be of therapeutic interest if TRAIL agonists are introduced in clinics.
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PMID:Redistribution of CD95, DR4 and DR5 in rafts accounts for the synergistic toxicity of resveratrol and death receptor ligands in colon carcinoma cells. 1548 Apr 30

Although colon carcinoma cells express Fas receptors, they are resistant to Fas-mediated apoptosis. Defects within the intracellular Fas signal transduction may be responsible. We investigated whether the Fas-associated phosphatase-1 (FAP-1), an inhibitor of Fas signal transduction, contributed to this resistance in colon carcinomas. In vivo, apoptosis of cancer cells was detected in situ using terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling (TUNEL). FAP-1, FasR, and Fas ligand (FasL) were detected using immunohistochemistry. In vitro, colon carcinoma cells were primarily cultured, and their sensitivity to Fas-mediated apoptosis was evaluated by treatment with agonistic anti-FasR CH11 IgM monoclonal antibody in the presence or absence of synthetic Ac-SLV (serine-leucine-valine) tripeptide. Fas-associated phosphatase-1 expression was detected in 20 out of 28 colon adenocarcinomas. In vivo, a positive correlation between the percentage of apoptotic tumour cells and the number of FasL-positive tumour infiltrating lymphocytes was observed in FAP-1 negative cancers, but not in FAP-1-positive ones. Primarily cultured colon cancer cells, which were refractory to CH-11-induced apoptosis, had higher expression of FAP-1 on protein and mRNA levels than the sensitive group. Resistance to Fas-mediated apoptosis in tumour cells could be abolished by Ac-SLV tripetides. Fas-associated phosphatase-1 expression protects colon cancer cells from Fas-mediated apoptosis, and blockade of FAP-1 and FasR interaction sensitises tumour cells to Fas-dependent apoptosis.
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PMID:Expression of FAP-1 by human colon adenocarcinoma: implication for resistance against Fas-mediated apoptosis in cancer. 1549 22

The platinum compound oxaliplatin has been shown to be an effective chemotherapeutic agent for the treatment of colorectal cancer. In this study, we investigate the molecular mechanisms of action of oxaliplatin to identify means of predicting response to this agent. Exposure of colon cancer cells to oxaliplatin resulted in G2/M arrest and apoptosis. Immunofluorescent staining demonstrated that the apoptotic cascade initiated by oxaliplatin is characterised by translocation of Bax to the mitochondria and cytochrome c release into the cytosol. Oxaliplatin treatment resulted in caspase 3 activation and oxaliplatin-induced apoptosis was abrogated by inhibition of caspase activity with z-VAD-fmk, but was independent of Fas/FasL association. Targeted inactivation of Bax or p53 in HCT116 cells resulted in significantly increased resistance to oxaliplatin. However, the mutational status of p53 was unable to predict response to oxaliplatin in a panel of 30 different colorectal cancer cell lines. In contrast, the expression profile of these 30 cell lines, assessed using a 9216-sequence cDNA microarray, successfully predicted the apoptotic response to oxaliplatin. A leave-one-out cross-validation approach was used to demonstrate a significant correlation between experimentally observed and expression profile predicted apoptosis in response to clinically achievable doses of oxaliplatin (R=0.53; P=0.002). In addition, these microarray experiments identified several genes involved in control of apoptosis and DNA damage repair that were significantly correlated with response to oxaliplatin.
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PMID:Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells. 1554 75


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