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)

Resident proteins that reside on the plasma membrane are continually exfoliated from the cell surface. Exfoliation is a selective, energy-dependent process that mediates intercellular communication. Ionizing radiation modulates the expression of many plasma membrane-bound growth regulators, including the "death" ligand, TNFSF6 (formerly known as FasL, CD95L). Here we report that ionizing radiation induces dose-dependent up-regulation of TNFSF6 on plasma membranes purified from SW620 cells, a TNFSF6-expressing colon cancer cell line. Serum-free medium conditioned by exposed and control cells was collected and exfoliated vesicles were obtained by ultracentrifugation. Western blot analysis of vesicles from unexposed cells and from cells treated with 10 Gy showed increased amounts of TNFSF6 compared to that on vesicles from unexposed cells. Cells treated with 4 Gy released vesicles having a low level of TNFSF6 on their surface relative to that on vesicles exfoliated from unexposed cells. When assayed for bioactivity, vesicles from unexposed cells induced the greatest level of apoptosis in TNFRSF6 (formerly known as FAS) receptor-bearing Jurkat cells (cell surviving fraction of 43.7 +/- 6.1; P < 0.05), followed by vesicles collected from cells treated with 4 Gy (79.6 +/- 2.6%; P < 0.05). Despite having a high level of TNFSF6 by Western analysis, vesicles collected from cells exposed to 10 Gy display minimal biological activity (77.9 +/- 3.2%; P < 0.05), suggesting that modification of the vesicle-associated ligand has occurred. Our results indicate that ionizing radiation increases the level of TNFSF6 exfoliated on extracellular vesicles. The data may provide a mechanism for abscopal and bystander effects after irradiation.
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PMID:Ionizing radiation alters Fas antigen ligand at the cell surface and on exfoliated plasma membrane-derived vesicles: implications for apoptosis and intercellular signaling. 1063 Sep 77

Cell death due to thymine (dThd) deficiency, associated with the cytotoxic action of 5-fluorouracil in colon cancer, is regulated in thymidylate synthase-deficient (TS(-)) human colon carcinoma cells via the Fas (CD95, APO-1) death receptor. This was demonstrated by inhibiting the loss in clonogenicity of TS(-) cells by anti-FasL and in enhanced survival of TS(-) clones selected for resistance to Fas-mediated apoptosis, following dThd deprivation. During thymineless stress in TS(-) cells, Fas ligand (FasL) is expressed, and its promoter (hFasLPr) is activated. Transactivation of hFasLPr, dependent upon dThd deficiency, was inhibited following mutation of the binding sites for NF-kappaB or AP-1 and by preventing NF-kappaB or AP-1 activation, which inhibited expression of FasL and enhanced clonogenic survival in stable transformants expressing IkappaBalphaM or DN-MEKK, respectively. These results demonstrate the crucial roles for NF-kappaB and AP-1 in the regulation of FasL in Fas-mediated thymineless death of colon carcinoma cells.
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PMID:Regulation of FasL by NF-kappaB and AP-1 in Fas-dependent thymineless death of human colon carcinoma cells. 1074 79

The counterattack hypothesis, suggesting that cancer cells express Fas ligand (FasL) and are able to kill Fas-expressing tumor-infiltrating activated T cells, was supported by reports of the killing of Jurkat cells by FasL-expressing human colon cancer cell lines. Through the use of an improved cytotoxic assay in which soluble FasL and FasL-transfected KFL9 cells were used as positive controls, we show that none of seven human colon cancer cell lines induce apoptosis of two Fas-expressing target cell lines, Jurkat and L1210-Fas cells. Moreover, in coculture experiments, cancer cell monolayers do not inhibit the growth of Fas-expressing lymphoid cells. Although FasL mRNA and protein were detected in the extracts of the colon cancer cell lines, flow cytometry and confocal microscopy failed to detect the protein on the surface of tumor cells. These results suggest that the counterattack of tumor-infiltrating T lymphocytes by cancer cells may not account for immune tolerance toward tumor cells.
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PMID:Cutting edge: the tumor counterattack hypothesis revisited: colon cancer cells do not induce T cell apoptosis via the Fas (CD95, APO-1) pathway. 1079 56

During tumour progression, cancer cells use diverse mechanisms to escape from apoptosis-inducing stimuli, which may include receptor internalization, inhibition of signal pathways, and regulation of specific sets of genes. Substantial numbers of colon cancer cells have been observed to express Fas/Fas ligand, but are resistant to Fas-mediated apoptosis, suggesting that colonic tumours might develop specific mechanisms to overcome Fas-mediated apoptosis. Recently, cellular FLICE-like inhibitory protein (cFLIP) has been identified as an endogenous inhibitor of Fas- or other receptor-mediated apoptosis and its altered high expression has a suspected association with tumour development or progression. In an effort to investigate the prevalence of cFLIP(L) alterations in colon carcinomas and their possible implications for the progression of colon cancers, cFLIP(L) expression was analysed in adenocarcinomas and adenomatous polyps of colon, with matched normal tissues, at RNA and protein levels, by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. cFLIP(L) transcripts were constitutively expressed in colon cancers and expression levels were significantly higher in carcinomas than in normal tissues (p<0.05). Overexpression of cFLIP(L) protein was found exclusively in carcinoma cells in all matched sets analysed and approximately three-fold induction was detected in cancer cells (p<0.05). The expression of cFLIP(L) protein was not significantly altered in adenomatous polyps compared with normal tissues. Taken together, these results strongly suggest that abnormal overexpression of cFLIP(L) is a frequent event in colon carcinomas and might contribute to in vivo tumour transformation.
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PMID:Increased expression of cFLIP(L) in colonic adenocarcinoma. 1132 36

Metastasis of colorectal carcinomas rarely occurs in cirrhotic livers. Our study investigated the influence of activated Kupffer cells from cirrhotic rat livers on hepatic colonization and FasR-mediated apoptosis of colon cancer cells. A rat colon cancer cell line, RCN-9, was used to inoculate rat livers. Treatment with conditioned media of Kupffer cells isolated from CCl(4)-induced cirrhotic rat livers (cirrhotic KCM) significantly reduced the incidence of hepatic colonization of RCN-9 cells. In vitro cytotoxicity of Kupffer cells and tumour infiltrating lymphocytes (TILs) on RCN-9 cells was evaluated using [(3)H]-release assay. RCN-9 cells were resistant to cytotoxicity mediated by cirrhotic Kupffer cells, but were sensitized to TIL-mediated killing after treatment with cirrhotic KCM. The specific killing induced by TILs was FasR-mediated, as it was inhibited by ZB4, an antagonistic anti-FasR antibody. In agreement, cirrhotic KCM increased recombinant Fas ligand-induced apoptosis of RCN-9 cells, and up-regulated FasR expression on RCN-9 cells as evaluated by RT-PCR and flow cytometry. These findings suggest that Kupffer cells in cirrhotic livers sensitize metastatic colon cancer cells to FasR-mediated apoptosis by up-regulating the receptors, which thus prepare them to be eliminated by infiltrating lymphocytes.
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PMID:Kupffer cells of cirrhotic rat livers sensitize colon cancer cells to Fas-mediated apoptosis. 1133 80

Expression of membrane-bound Fas ligand (mFasL) on colon cancer cells serves as a potential mechanism to inhibit host immune function by inducing apoptosis of host lymphocytes. Membrane-bound FasL can be cleaved and released as a soluble mediator (sFasL), which may spread the apoptosis induction effect. Our study examined whether colon adenocarcinoma cells release sFasL, and induce apoptosis of host lymphocytes without direct cell-cell contact. In 12 consecutive patients with colon adenocarcinoma mFasL was identified in the tumours, sFasL was measured in the sera and apoptosis identified in tumour-infiltrating and peripheral blood lymphocytes. To analyse the function of sFasL, colon cancer cells were primarily cultured; sFasL was isolated from supernatants, measured, incubated with Fas-bearing Jurkat cells, and the resulting apoptosis was analysed. Serum levels of sFasL were significantly elevated in all colon cancer patients with mFasL expression in tumour tissues (n = 8). In these patients, the number of apoptotic lymphocytes was significantly increased within tumour and peripheral blood. Furthermore, sFasL was present in the corresponding supernatants and induced apoptosis of Jurkat cells in a dose-dependent manner. These findings suggest that mFasL-positive colon cancer cells release sFasL, and thus may induce apoptosis of host lymphocytes as a potential mechanism for immune evasion.
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PMID:Soluble Fas ligand released by colon adenocarcinoma cells induces host lymphocyte apoptosis: an active mode of immune evasion in colon cancer. 1159 78

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2 ligand (Apo2L) has been identified as important in promoting programmed cell death in breast and colon cancer xenografts. More importantly, normal liver tissue appears not to be susceptible to the cytotoxic effects of TRAIL/Apo2L, although activation of the related Fas ligand receptor system is known to promote massive liver apoptosis terminating in fulminant hepatitis. In the present study, we investigated the therapeutic potential of TRAIL/Apo2L gene therapy in hepatocellular carcinoma (HCC) and evaluated its side effects in an immune-competent mouse model. Intratumoral administration of the TRAIL/Apo2L vector by electroporation elevated serum TRAIL/Apo2L through at least day 28 after gene therapy and significantly inhibited the growth not only of the HCC directly administered TRAIL/Apo2L vector, but also of distant subcutaneous HCC. In addition, intratumoral administration of the TRAIL/Apo2L vector inhibited spontaneous lung metastasis. Serum alanine aminotransferase was mildly elevated by TRAIL/Apo2L gene therapy, but without showing such histological signs as TUNEL staining. These results demonstrate that TRAIL/Apo2L gene therapy for HCC by electroporation in vivo is efficient without significant side effects, and is thus promising for use in future clinical trials.
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PMID:Electroporation-mediated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L gene therapy for hepatocellular carcinoma. 1181 83

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

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

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


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