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)

Pancreatic cancer cells are usually resistant to apoptosis mediated by intrinsic or extrinsic factors. BAG-3 (Bis, CAIR), which was identified as a BAG-1-related protein, is a novel modulator of cellular anti-apoptotic activity that functions through its interaction with Bcl-2. In this study we analyzed BAG-3 expression in human pancreatic cancer tissues and cell lines. BAG-3 mRNA was expressed at moderate to high levels in all pancreatic cancer samples, but at low levels in normal pancreas tissues. In situ hybridization and immunohistochemistry analysis revealed that BAG-3 was present in the cancer cells within the pancreatic tumor mass. When BAG-3 mRNA was analyzed in other gastrointestinal cancers (hepatocellular carcinoma; esophageal, stomach and colon cancer), no difference was found from their corresponding normal controls. In pancreatic cancer cells, BAG-3 mRNA expression levels were strongly induced after heat stress, but not in response to members of the tumor necrosis factor (TNF)-alpha family (TNF-alpha, TRAIL, FasL). These findings indicate that in pancreatic cancer, in contrast to other gastrointestinal malignancies, increased levels of BAG-3 might function to block apoptosis. This characteristic of pancreatic cancer might contribute to its more aggressive growth behavior and poor responsiveness to treatment in vivo.
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PMID:The anti-apoptotic protein BAG-3 is overexpressed in pancreatic cancer and induced by heat stress in pancreatic cancer cell lines. 1151 73

In order to define genes which mediate liver tropism of colon cancer metastasis we have compared the transcriptional profile of 5600 full-length genes using the Affymetrix HuGene FL array technology of the non-metastatic colon cancer cell lines KM12C and the two metastatic cell lines, KM12SM and KM12L4A, which are derived from KM12C. We present data on genes which are up- and downregulated in the metastatic cell line and those which are selectively upregulated in one of the metastatic cell lines. We have sub-grouped the deregulated genes into different categories, such as immune response, modulation of transcription, enzymes, cell cycle/apoptosis, interferon- and tumor necrosis factor-regulated genes, tumor antigens and transmembrane receptors, intracellular signaling, cytoskeleton and extracellular matrix associated proteins, 'others' and genes of unknown function.
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PMID:Identification of metastasis-associated genes by transcriptional profiling of metastatic versus non-metastatic colon cancer cell lines. 1172 90

Alpha-tocopheryl succinate (alpha-TOS), a redox-inactive analogue of vitamin E, is a strong inducer of apoptosis, whereas alpha-tocopherol (alpha-TOH) lacks apoptogenic activity (J. Neuzil et al., FASEB J., 15: 403-415, 2001). Here we investigated the possible antineoplastic activities of alpha-TOH and alpha-TOS and further explored the potential of alpha-TOS as an antitumor agent. Using nude mice with colon cancer xenografts, we found that alpha-TOH exerted modest antitumor activity and acted by inhibiting tumor cell proliferation. In contrast, alpha-TOS showed a more profound antitumor effect, at both the level of inhibition of proliferation and induction of tumor cell apoptosis. alpha-TOS was nontoxic to normal cells and tissues, triggered apoptosis in p53(-/-) and p21(Waf1/Cip1(-/-)) cancer cells, and exerted a cooperative proapoptotic activity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) due to differences in proapoptotic signaling. Finally, alpha-TOS cooperated with tumor necrosis factor-related apoptosis-inducing ligand in suppression of tumor growth in vivo. Vitamin E succinate is thus a potent and highly specific anticancer agent and/or adjuvant of considerable therapeutic potential.
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PMID:Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo. 1189 20

We have previously established that insulin-like growth factor (IGF)-I, -II and insulin exert a strong protective effect against tumor necrosis factor-alpha (TNF)-induced apoptosis in interferon-gamma (IFN)-sensitized HT29-D4 human colon carcinoma cells. In this study, we report that this effect was still operative when cells were cultured in the absence of integrin- and E-cadherin-mediated cell-extracellular matrix and cell-cell interactions. In this model, IGF-I did not activate the focal adhesion kinase, whereas it induced tyrosine phosphorylation of the insulin receptor substrate-1 and activation of the extracellular signal-related kinase 1 and 2, p38, phosphatidylinositol 3'-kinase and protein kinase B/Akt. However, the use of specific inhibitors indicated that these pathways did not play a role in the adhesion-independent IGF-I anti-apoptotic signal. In contrast, inhibition of the NF-kappaB activation induced a complete reversal of the IGF-I anchorage-independent protective effect. Correspondingly, IGF-I markedly enhanced the TNF- and IFN/TNF-induced NF-kappaB-dependent interleukin-8 production. Our results provide evidence that IGF-I induces resistance against cytokine-induced cell death even in the absence of cell adhesion-mediated signaling. NF-kappaB appears to be a key mediator of this anti-apoptotic effect that should contribute to the resistance of colon cancer cells to immune-destruction during metastasis.
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PMID:Prevention of cytokine-induced apoptosis by insulin-like growth factor-I is independent of cell adhesion molecules in HT29-D4 colon carcinoma cells-evidence for a NF-kappaB-dependent survival mechanism. 1205 82

We investigated supra-additive cytotoxic effects of 5-fluorouracil (5FU) on gastric and colon cancer cells with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in vitro. p53 wild- and mutant-type gastric and colon cancer cell lines were treated by 5FU alone, TRAIL alone, and a combination of 5FU and TRAIL, and cell viability after each treatment was determined by MTT assay. The p53 wild-type cells were more sensitive to 5FU alone or to TRAIL alone than p53 mutant-type cells. The cell growth inhibitory effects of the combined treatment were supra-additive and more significant in proportion to the increasing concentrations of TRAIL as compared with 5FU alone both in p53 wild- and mutant-type cells. Furthermore, TRAIL could cause a decrease in 5FU IC(50) to within the range of clinically relevant doses, particularly in p53 wild-type cells. This is the first demonstration of the supra-additive antitumor activity of 5FU with TRAIL on gastric cancer cells, giving evidence that TRAIL can reduce the requirement for 5FU that ultimately results in minimizing risks for systemic side effects while increasing the antitumor activity of 5FU, suggesting the clinical applicability of this combination for gastric and colon cancers.
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PMID:Supra-additive antitumor activity of 5FU with tumor necrosis factor-related apoptosis-inducing ligand on gastric and colon cancers in vitro. 1216 12

The inducible cyclooxygenase-2 (COX-2) gene regulates prostaglandin biosynthesis,is up-regulated in colorectal cancers, and can influence apoptotic susceptibility. We determined whether forced COX-2 expression modulates apoptosis induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of tumor necrosis factor ligand family, and examined determinants of the apoptotic pathway, including membrane death receptors (DR-4 and DR-5). HCT-15 colon cancer cells lacking endogenous COX-2 proteins were stably transfected with the COX-2 cDNA and incubated with TRAIL. Forced COX-2 expression significantly attenuated TRAIL-induced apoptosis and was associated with transcriptional repression of DR-5 and up-regulation of Bcl-2. COX-2 transfectants showed reduced DR-5 mRNA and protein expression as well as reduced caspase-8, caspase-3, and caspase-9 activation relative to parental cells. Sulindac sulfide treatment restored DR-5 expression and, when combined with TRAIL, reduced cell viability to a greater extent than did either drug alone. In summary, modulation of DR-5 and Bcl-2 levels by COX-2 attenuates TRAIL-induced apoptosis and represents a novel mechanism of intrinsic drug resistance in human colon cancer cells.
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PMID:Cyclooxygenase-2 overexpression inhibits death receptor 5 expression and confers resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human colon cancer cells. 1220 39

To evaluate resistance that develops in cancer cells during treatment with adenoviral vectors expressing proapoptotic genes, we repeatedly treated the human colon cancer cell line DLD1 with adenoviral vectors expressing the human Bax gene and the human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. DLD1 cells resistant to the Bax- or TRAIL-expressing adenoviral vectors were then selected and designated as DLD1/Bax-R or DLD1/TRAIL-R cells, respectively. Further study showed that resistance in DLD1/Bax-R cells was caused by resistance to adenoviral infection, which can be overcome by dose escalation of the adenoviral vectors. However, resistance in DLD1/TRAIL-R cells was caused by resistance to the TRAIL gene. Therefore, different mechanisms are involved in the development of resistance during adenovirus-mediated proapoptotic gene therapy. A survey of molecules involved in TRAIL- or Bax-mediated apoptotic pathways showed no significant change in expression of death receptors, death decoy receptors; FLIP; Bcl-2; Bcl-xS; Bax; Bak; XIAP or caspase-2, -7, -8, or -9 in either DLD1/Bax-R or DLD1/TRAIL-R cells. Bcl-xL expression detected in both mRNA and protein level assays was three times higher in DLD1/TRAIL-R cells than in parental or DLD1/Bax-R cells. However, transfection of DLD1 cells with the Bcl-xL gene showed that overexpression of Bcl-xL is not sufficient for the resistance. Moreover, DLD1/Bax-R cells were sensitive to adenoviral vectors that expressed the TRAIL gene, but resistant to adenoviral vectors that expressed the Bak gene. In contrast, DLD1/TRAIL-R cells were sensitive to adenoviral vectors that expressed either Bax or Bak gene. Thus, alternative application of adenoviral vectors that expressed proapoptotic genes in different pathways or different cell killing models may delay or prevent development of resistance in adenovirus-mediated proapoptotic gene therapy.
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PMID:Mechanisms involved in development of resistance to adenovirus-mediated proapoptotic gene therapy in DLD1 human colon cancer cell line. 1221 94

The mechanisms by which surgery increases metastatic proliferation remain poorly characterized, although endotoxin and immunocytes play a role. Recent evidence suggests that endothelial adherence of tumor cells may be important in the formation of metastases. Soluble receptors of interleukin-6 (sIL-6R) shed by activated neutrophils exert IL-6 effects on endothelial cells, which are unresponsive under normal circumstances. This study examined the hypothesis that sIL-6R released by surgical stress increases tumor cell adherence to the endothelium. Neutrophils (PMN) were stimulated with lipopolysaccharide, C-reactive protein (CRP), and tumor necrosis factor-alpha. Soluble IL-6R release was measured by enzyme-linked immunosorbent assay. Colonic tumor cells transfected with green fluorescent protein and endothelial cells were exposed to sIL-6R, and tumor cell adherence and transmigration were measured by fluorescence microscopy. Basal release of sIL-6R from PMN was 44.7 +/- 8.2 pg/ml at 60 min. This was significantly increased by endotoxin and CRP (131 +/- 16.8 and 84.1 +/- 5.3, respectively; both P < 0.05). However, tumor necrosis factor-alpha did not significantly alter sIL-6R release. Endothelial and tumor cell exposure to sIL-6R increased tumor cell adherence by 71.3% within 2 h but did not significantly increase transmigration, even at 6 h. Mediators of surgical stress induce neutrophil release of a soluble receptor for IL-6 that enhances colon cancer cell endothelial adherence. Since adherence to the endothelium is now considered to be a key event in metastatic genesis, these findings have important implications for colon cancer treatment strategies.
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PMID:Soluble interleukin 6 receptor (sIL-6R) mediates colonic tumor cell adherence to the vascular endothelium: a mechanism for metastatic initiation? 1238 57

Thymidine phosphorylase (TP; also known as platelet-derived endothelial cell growth factor, PD-ECGF) is an angiogenic factor that is chemotactic for endothelial cells and has been found to induce neovascularization in vivo. TP is frequently overexpressed in human solid tumors, where its expression has been correlated with increased tumor microvessel density, invasion, and metastasis, and shorter patient survival. In this report, TP activity in the WiDr colon carcinoma cell line was found to be induced 100-fold by tumor necrosis factor (TNFalpha), a secretory product of activated macrophages that has indirect angiogenic activities. Increased TP activity was accompanied by increased TP mRNA levels and without an increase in mRNA stability. TNFalpha-induced TP mRNA levels were reduced by mithramycin, a DNA-binding transcription inhibitor specific for GC-rich sequences. Transcriptional regulation by TNFalpha was confirmed by transient transfection of WiDr with upstream TP sequences in a luciferase reporter construct. Deletion analysis of the reporter pinpointed two regions of the TP promoter with regulatory elements for both TNFalpha-inducible and basal expression, and they contained, respectively, three and one consensus binding sites for the Sp1-family of transcription factors. One additional region contributed only to basal TP expression, and it contained three Sp1 sites. TNFalpha-induced TP expression decreased when point mutations were made in three of the four Sp1 sites postulated to contribute to both basal and TNFalpha-inducible expression. Electrophoretic mobility shift assays further demonstrated binding of nuclear Sp1 to these three sites. Sp1-binding activity was also increased in cells treated with TNFalpha. These studies establish a role for Sp1 in the regulation of expression of the angiogenic factor TP in colon cancer WiDr cells.
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PMID:The Sp1 transcription factor contributes to the tumor necrosis factor-induced expression of the angiogenic factor thymidine phosphorylase in human colon carcinoma cells. 1246 67

Flavopiridol is one of the first cyclin-dependent kinase inhibitors undergoing clinical tests. We found that the combination treatment of flavopiridol (100-500 nM) with tumor necrosis factor (TNF)-alpha (10 ng/ml) induced a rapid and eminent apoptosis, 20 +/- 5% in 6-h treatment, in a human non-small cell lung carcinoma cell line, A549, as determined by the increase of sub-G(1) fraction in flow cytometry. A similar observation was also made in human colon cancer cell lines, HCT-116 and HCT-15, but not in Rat2, a rat fibroblast cell line. In A549 cells, the cytotoxic synergy by the combination treatment involved the activation of caspase-1, caspase-3, and caspase-8 and generated huge chromosomal degradation. The treatment schedules were so important that only the treatments of flavopiridol concomitantly with or followed by TNF-alpha showed the pronounced apoptosis in A549 cells. Prior treatment of TNF-alpha inhibited the apoptosis by the following combination treatment, leading to little cell death. Yet, such inhibition was reversed when 100 microM of 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole, a transcription inhibitor, was present during the TNF-alpha pretreatment, suggesting that the inhibitory pretreatment of TNF-alpha might involve antiapoptotic gene expression at the transcriptional level. TNF-alpha treatment resulted in nuclear factor (NF)-kappa B activation, revealed by NF-kappa B activity reporter assay. In contrast, flavopiridol was found to inhibit the NF-kappa B-dependent gene transcription, which might give an explanation for the synergistic effect of flavopiridol with TNF-alpha. TNF-related apoptosis-inducing ligand (TRAIL; 100 ng/ml) also caused a rapid and strong cytotoxic synergy with flavopiridol. In contrast to TNF-alpha, however, all of the treatment sequences supported the synergy by TRAIL and flavopiridol. The combination of flavopiridol with TNF-alpha or TRAIL may be of use for the development in cancer therapy.
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PMID:Rapid induction of apoptosis by combination of flavopiridol and tumor necrosis factor (TNF)-alpha or TNF-related apoptosis-inducing ligand in human cancer cell lines. 1256 5


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