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)

Estrogen receptor beta (ERbeta) mediated system was tested in three colon cancer cell lines with different sensitivities. These cell lines express ERbeta and androgen receptor (AR) but not the classic estrogen receptor ERalpha. Combinations of ERbeta ligands such as estradiol (E(2)), 17 epiestriol (17E(3)), quercetin (Q) with tamoxifen (TMX) showed marked growth inhibition. The IC(50) were: 2. 0+/-0.3x10(-15), 3.0+/-1.3x10(-10) and 1.2+/-0.5x10(-14) M for DLD-1, DLD-1/5FU and DLD-1/FdUrd, respectively (TMX+E(2) treatment, mean+/-SD, n=3). The IC(50) of TMX+17E(3) were 3.5+/-1.8x10(-8), 2. 6+/-0.9x10(-8) and 1.4+/-1.1x10(-14) M and that of TMX+Q treatment were 3.4+/-2.1x10(-9), 3.6+/-0.2x10(-9) and 2.6+/-1.1x10(-9) M, respectively. This inhibition was significantly different from single agent treatment at the probability level of P<0.002. Thymidylate synthase expression and survivin expression were also markedly inhibited. The inhibition was highest with TMX+Q and lowest with TMX+dehydroepiandrosterone (DHEA). The expression of telomerase was also inhibited by TMX but combination with ERbeta agonists reversed the inhibition. The cellular sensitivity to 5FU was increased: TMX+E(2), TMX+17E(3) and TMX+Q were 1.7+/-0.5x10(-5), 8. 4+/-3.2x10(-8), 8.2+/-2.9x10(-8) and 6.3+/-3.3x10(-8) M for DLD-1 cells and 7.7+/-4.8x10(-5), 9.1+/-4.9x10(-7), 1.5+/-0.3x10(-9) and 5. 7+/-2.2x10(-8) M for DLD-1/5FU. DLD-1/FdUrd cells had IC(50) of 8. 5+/-6.1x10(-5), 1.8+/-0.8x10(-8), 37+/-1.1x10(-9) and 1.6+/-1. lx10(-9) M (mean+/-SD) for the control, TMX+E(2), TMX+17E(3) and TMX+Q. The present data indicate that ERbeta ligands in combination with TMX may have tumor static effects on colon cancer cells.
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PMID:Tamoxifen and gonadal steroids inhibit colon cancer growth in association with inhibition of thymidylate synthase, survivin and telomerase expression through estrogen receptor beta mediated system. 1107 14

The regulation of apoptotic cell death may have a profound effect on the pathogenesis and progression of colon cancer. Survivin, a member of the inhibitor of apoptosis gene family, has been detected in fetal tissue and in a variety of human malignancies. In the current study, we investigated survivin expression by an immunohistochemical approach in benign, hyperplastic, premalignant, and malignant lesions of the colon. Survivin was detected in all cases of normal colonic mucosa (20/20), hyperplastic polyps (20/20), adenomatous polyps (20/20), and in both well differentiated and moderately differentiated colonic adenocarcinomas (20/20). In the normal colonic mucosa, survivin expression was mostly restricted to the base of the colonic crypts. All epithelial cells showed uniformly intense staining for survivin in hyperplastic polyps. By contrast, adenomas and adenocarcinomas showed a heterogeneous staining pattern with cell-to-cell, gland-to-gland, and regional variability in the intensity of survivin staining. In contrast to the basal preponderance of staining in normal colonic mucosa, numerous survivin positive cells were present at the luminal surface of hyperplastic polyps, adenomatous polyps, and adenocarcinomas. In conclusion, the expression of survivin is not a specific marker of adenocarcinoma of the colon but does show characteristic and reproducible patterns of expression in non-neoplastic proliferative lesions and in normal colonic mucosa.
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PMID:Expression of survivin in normal, hyperplastic, and neoplastic colonic mucosa. 1117 5

Survivin, a novel inhibitor of apoptosis, is expressed in cancer cells and not in normal adult tissues, and is recognised as a potential target in anticancer therapy. The induction of a natural antisense of survivin, effector cell protease receptor-1 (EPR-1), in a human colon cancer cell line resulted in a downregulation of survivin expression, with a similar decrease in cell proliferation, an increase in apoptosis and an increase in the sensitivity to anticancer agents. In addition, subcutaneous (s.c.) tumours from EPR-1 transfectants showed a significant reduction in size compared with parental cells, and this antitumour efficacy was further enhanced in combination with anticancer agents. These findings suggest that regulation of survivin by the induction of EPR-1 cDNA may have significant potential as a therapy for human colon cancer.
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PMID:Downregulation of survivin expression by induction of the effector cell protease receptor-1 reduces tumor growth potential and results in an increased sensitivity to anticancer agents in human colon cancer. 1244 Dec 69

Activation of protein kinase C (PKC) prevents apoptosis in certain cells; however, the mechanisms are largely unknown. Inhibitors of apoptosis (IAP) family members, including NAIP, cIAP-1, cIAP-2, XIAP/hILP, survivin, and BRUCE, block apoptosis by binding and potently inhibiting caspases. Activation of NF-kappa B contributes to cIAP-2 induction; however, the cellular mechanisms regulating cIAP-2 expression have not been entirely defined. In this study, we examined the role of the PKC and NF-kappa B pathways in the regulation of cIAP-2 in human colon cancers. We found that cIAP-2 mRNA levels were markedly increased in human colon cancer cells by treatment with the phorbol ester, phorbol-12-myristate-13-acetate (PMA), or bryostatin 1. Inhibitors of the Ca2+-independent, novel PKC isoforms, but not inhibitors of MAPK, PI3-kinase, or PKA, blocked PMA-stimulated cIAP-2 mRNA expression, suggesting a role of PKC in PMA-mediated cIAP-2 induction. Pretreatment with the PKC delta-selective inhibitor rottlerin or transfection with an antisense PKC delta oligonucleotide inhibited PMA-induced cIAP-2 expression, whereas cotransfection with a PKC delta plasmid induced cIAP-2 promoter activity, which, taken together, identifies a role for PKC delta in cIAP-2 induction. Treatment with the proteasome inhibitor, MG132 or inhibitors of NF-kappa B (e.g. PDTC and gliotoxin), decreased PMA-induced up-regulation of cIAP-2. PMA-induced NF-kappa B activation was blocked by either GF109203x, MG132, PDTC, or gliotoxin. Moreover, overexpression of PKC delta-induced cIAP-2 promoter activity and increased NF-kappa B transactivation, suggesting regulation of cIAP-2 expression by a PKC delta/NF-kappa B pathway. In conclusion, our findings demonstrate a role for a PKC/NF-kappa B-dependent pathway in the regulation of cIAP-2 expression in human colon cancer cells. These data suggest a novel mechanism for the anti-apoptotic function mediated by the PKC delta/NF-kappa B/cIAP-2 pathway in certain cancers.
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PMID:Induction of cIAP-2 in human colon cancer cells through PKC delta/NF-kappa B. 1452 59

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac have chemopreventive activity against colorectal tumors. Although the molecular mechanism has not been fully established, it is thought to involve the ability of NSAIDs to induce apoptosis. Because the majority of colon carcinomas are known to overexpress antiapoptotic proteins such as survivin and Bcl-2 and show only limited ability to undergo apoptosis, we hypothesized that the ability of sulindac to cause regression of adenomas and to inhibit colon carcinogenesis is mediated, at least in part, by down-regulation of one or more of these antiapoptotic proteins. To test this hypothesis, we exposed HT-29 colon carcinoma cells to sulindac. Sulindac induced a sustained decrease in mRNA and protein expression for survivin but not for Bcl-2. This finding suggests that sulindac is selectively acting through a survivin-related pathway. This is consistent with our earlier finding that inhibition of the beta-catenin:T-cell factor 4 (Tcf-4) pathway by the adenomatous polyposis coli protein down-regulates survivin expression and with recent evidence that sulindac induces beta-catenin degradation, which would reduce Tcf-4 activation. This suggests that the beta-catenin:Tcf-4:survivin mechanism may be a useful target for therapy or chemoprevention of colon cancer.
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PMID:The chemopreventive agent sulindac attenuates expression of the antiapoptotic protein survivin in colorectal carcinoma cells. 1461 Feb 17

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

Tumor development and progression is driven by the accumulation of somatic genetic alterations. Two major pathways have been suggested in colon tumorigenesis. The first one, the APC/B-catenin pathway consists of chromosomal imbalance (Instability) and therefore accumulation of different oncogenes and tumor supressor genes mutations associated with morphological changes. The second one is characterized by "DNA mismatch repair genes" damage with subsequent accumulation of somatic genetic predictive markers of distant metastasis using tissue microarrays in T2N0 colon cancer. In our series, we detected overexpression of survivin, CDK1, MIB1 and topoisomerase IIa in metastatic tumors.
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PMID:[Predictive molecular marker of distant metastasis in colorectal cancer]. 1502 5

Members of the inhibitor of apoptosis protein (IAP) family including survivin, are expressed in many tumors. However, age-related changes in their expression in cancer have not been clarified. Thus, we investigated the expression of mRNA-coding for IAP family proteins in colon cancer samples from young (<70 years of age) and elderly (>70 years) patients by real-time quantitative RT-PCR. Samples were collected from cases with well-differentiated adenocarcinoma or moderately differentiated adenocarcinoma and their adjacent normal epithelial tissue. Well-differentiated adenocarcinoma tended to express higher levels of survivin than normal mucosa, and expression in moderately differentiated adenocarcinoma was significantly greater than in normal mucosa in samples from both groups of patients ( p<0.05, respectively). When samples were compared between the different age groups, the normal mucosa exhibited similar levels of survivin expression. However, samples from older patients showed a significantly higher level of expression than those from younger patients in well and moderately differentiated adenocarcinomas ( p<0.05, respectively). In contrast, the levels of expression of cIAP1, cIAP2, and NAIP in the cancerous tissues were lower than those found in normal mucosa regardless of age. As for age-related changes, the expression of cIAP2 in normal mucosa and moderately differentiated adenocarcinoma was stronger in the elderly group than the young group ( p<0.05, respectively), and NAIP expression in well-differentiated adenocarcinoma was higher in the young group than the elderly group ( p<0.05). XIAP expression was similar in normal and cancerous tissues in both the young and elderly groups. These results suggest that the expression of IAP family proteins, especially survivin, is associated with the age-related biological characteristics of colon cancer.
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PMID:Expression of IAP family proteins in colon cancers from patients with different age groups. 1513 17

The aim of this study is to assess the effects of DNA methylation and histone acetylation, alone or in combination, on the expression of several tumor-associated genes and cell cycle progression in two established human colon cancer cell lines: Colo-320 and SW1116. Treatments with 5-aza-2-deoxycytidine (5-aza-dC) and trichostatin A, alone or in combination, were applied respectively. The methylation status of the CDKN2A promoter was determined by methylation-specific PCR, and the acetylated status of the histones associated with the p21WAF1 and CDKN2A genes was examined by chromatin immunoprecipitation. The expression of the CDKN2A, p21WAF1, p53, p73, APC, c-myc, c-Ki-ras and survivin genes was detected by real-time RT-PCR and RT-PCR. The cell cycle profile was established by flow cytometry. We found that along with the demethylation of the CDKN2A gene promoter in both cell lines induced by 5-aza-dC alone or in combination with TSA, the expression of both CDKN2A and APC genes increased. The treatment of TSA or sodium butyrate up-regulated the transcription of p21WAF1 significantly by inducing the acetylation of histones H4 and H3, but failed to alter the acetylation level of CDKN2A-associated histones. No changes in transcription of p53, p73, c-myc, c-Ki-ras and survivin genes were observed. In addition, TSA or sodium butyrate was shown to arrest cells at the G1 phase. However, 5-aza-dC was not able to affect the cell cycle progression. In conclusion, regulation by epigenetic modification of the transcription of tumor-associated genes and the cell cycle progression in both human colon cancer cell lines Colo-320 and SW1116 is gene-specific.
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PMID:Epigenetic modification regulates both expression of tumor-associated genes and cell cycle progressing in human colon cancer cell lines: Colo-320 and SW1116. 1522 15

Pancreatic ductal cancer has higher angiotensin II concentrations compared with normal pancreas or other solid tumors. This study examined angiotensin II type 1 (AT1) receptor expression and the role of angiotensin II in proliferation and survival of human pancreatic cancer cells. All three pancreatic cancer cell lines studied, from well to poorly-differentiated types, HPAF-II, AsPC-1, and Panc-1, showed strong expression of AT1 receptor. In contrast, HT-29 human colon cancer cells showed extremely weak expression. Angiotensin II stimulated the growth of pancreatic cancer cells through MAP kinase activation but had no significant effect on proliferation of HT-29 colon cancer cells. In addition, angiotensin II significantly prevented cisplatin (CDDP)-induced apoptosis through NF-kappaB activation and the subsequent production of anti-apoptotic molecules, including survivin and Bcl-XL, in pancreatic cancer cells. These findings suggest that angiotensin II plays a role in the growth and chemoresistance of AT1-positive pancreatic cancer cells through its action as a potent mitogen and anti-apoptotic molecule.
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PMID:Angiotensin II activates MAP kinase and NF-kappaB through angiotensin II type I receptor in human pancreatic cancer cells. 1537 32


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