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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the biological function of p53 in colon carcinoma cells, a wild-type p53 expression plasmid under the control of the human cytomegalovirus promoter was stably transfected into the human colon adenocarcinoma cell line WiDr, which carries a mutation of the p53 gene at codon 273. Exogenous wild-type p53 transcripts were detected at various expression levels in 8 of 117 G418-resistant clones. The growth rates of the wild-type p53+ clones in culture did not change significantly. The efficiency of colony formation in soft agar, however, was completely suppressed in two wild-type p53+ clones. This is the first to demonstrate the feasibility of stable transfection of the wild-type p53 gene under the control of non-inducible promoter in human colon cancer cells. The major alteration found was that wild-type p53+ cells which were incubated with anti-Fas IgM showed marked cytolysis with preferential over-expression of wild-type p53 accompanied by overexpression of a cyclin-dependent kinase inhibitor, WAF1, whereas the endogenous mutant p53 retained its expression level. The findings suggest that a Fas-initiated pathway is incidentally linked to a p53-dependent apoptotic pathway through the reconstituted wild-type p53 gene in WiDr cells. This model should help elucidating the additional role of the p53 tumor suppressor gene and the mechanism of apoptosis in colon carcinoma cells.
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PMID:Induction of Fas-mediated apoptosis in p53-transfected human colon carcinoma cells. 747 11

Transforming growth factor-beta (TGF-beta) inhibits cell cycle progression of many types of human cells by arresting them in the G1 phase of the cell cycle. The arrest is mediated through interactions of various cyclin-dependent protein kinases (CDKs) and their inhibitors. We demonstrate that treatment with TGF-beta induces increased levels of WAF1/Cip1/p21, a potent inhibitor of various cyclin-CDK kinase activities, in two colon cancer cell lines (LS1034 and LS513), which are sensitive to TGF-beta-induced growth arrest. The induction in at least one of these cell lines (LS1034,p53-) is p53-independent. No WAF1 induction was observed after TGF-beta treatment in a third cell line (HT-29), which is completely insensitive to the cytoinhibitory effect of TGF-beta. In both LS513 and LS1034, WAF1 induction correlated with reduced cyclin E-associated kinase activity in vitro and suppression of the retinoblastoma susceptibility gene (Rb) protein phosphorylation in vivo. In addition, WAF1 was physically associated with cyclin E in the two sensitive cell lines. These results suggest that WAF1/Cip1/p21 is a mediator of cellular sensitivity to TGF-beta.
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PMID:Potential role of WAF1/Cip1/p21 as a mediator of TGF-beta cytoinhibitory effect. 789 Jun 1

The myc gene family has been implicated in multiple cell processes including proliferation, differentiation, tumorigenesis, and apoptosis. For its cellular growth promoting function, Myc must heterodimerize with Max. To study the effect of Myc inactivation on the growth and differentiation properties of epithelial tumor cells, we transfected the H-630 human colon cancer cell line with bm-max, a mutant Max protein in which DNA-binding activity has been abolished. Cells expressing high levels of bm-Max grow poorly, and the morphology of both colonies and single cells is altered. Moreover, increased bm-Max expression results in a prolonged G alpha/G1 phase accompanied by induced expression of p21 (WAF1/CIP1), elevated levels of alkaline phosphatase (ALP) activity, and accumulation of large fat granuli within the cells. These distinctive cell characteristics are associated with differentiation processes in numerous malignant cell lines. The results of this study support a model in which sequestering of endogenous Myc and Max proteins into "basic mutant" dimers lacking DNA-binding activity is sufficient both to inhibit proliferation and to induce changes in cell behavior consistent with differentiation.
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PMID:c-Myc inactivation by mutant Max alters growth and morphology of NCI-H-630 colon cancer cells. 884 36

Camptothecin (CPT) traps covalent DNA topoisomerase I-linked DNA single-strand breaks (cleavable complexes). To determine the differences in DNA damage signalling leading to differential sensitivity to CPT, two human colon cancer cell lines, SW620 and KM12, with nonfunctional p53 and the same level of topoisomerase I cleavable complex formation but differential sensitivity to CPT (Cancer Res. 56:4430-7; 1996) were studied. The levels of mRNA expression of DNA damage-inducible or death-related genes were measured at different times after CPT treatment. KM12 cells exhibited 3-fold higher basal levels of BCL-2 mRNA. Consistently, secondary DNA fragmentation, quantitated using a filter elution assay, was detected 24 h later and was 2-4-fold lower in KM12 cells than in SW620 cells. No induction of BAX was detected in either cell line. Consistent with the absence of functional p53, p21CIP1/WAF1 and GADD45 genes were not induced within the first 24 h. However, in SW620 cells, both mRNA levels were increased more than 10-fold at 48 h. The BCL-2-related gene MCL-1 and topoisomerase II mRNA were induced at 24 h, and topoisomerase I mRNA levels increased 3-fold at 48 h, only in SW620 cells. We conclude that cellular response to CPT-induced DNA damage can involve p53-independent pathways leading to the induction of p53-effector genes. Induction of these genes at the onset of apoptosis is associated with CPT sensitivity.
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PMID:Differential GADD45, p21CIP1/WAF1, MCL-1 and topoisomerase II gene induction and secondary DNA fragmentation after camptothecin-induced DNA damage in two mutant p53 human colon cancer cell lines. 893 95

We have previously shown that p53 disruption sensitizes certain cancer cell types to cisplatin (CDDP) (Fan et al., 1995). In the present study we investigated the role of the p53 downstream effector, p21CIP1/WAF1 (p21), in this sensitization. Studies were performed in human colon cancer HCT-116 cells and murine embryonic fibroblasts (MEF) with intact versus disrupted p21 genes. For comparison, HCT-116 cells lacking p53 function were also prepared through stable transfection with the human papillomavirus type-16 E6 gene. HCT-116/E6 cells were found to be more sensitive than control transfectants to CDDP and another DNA crosslinking agent, nitrogen mustard (HN2). HCT-116 cells with disrupted p21 genes also exhibited greater CDDP and HN2-sensitivity than parental HCT-116 cells. In contrast, the clonogenic survival of HCT-116 cells exposed to ionizing radiation, adriamycin, taxol or vincristine was not affected by p53 or p21 disruption. Sensitization of HCT-116/p21-/- cells to CDDP and HN2 was not limited to the HCT-116 cell background since MEF from p21 knockout mice were also more sensitive to these DNA crosslinking agents. Investigations into a possible cause of this enhanced sensitivity revealed that HCT-116 cells lacking p53 or p21 function exhibited a reduced ability to repair cisplatin-damaged CAT-reporter plasmids transfected into the cells. In addition, we found that HCT-116/p21-/- cells were much more susceptible to HN2-induced cell cycle delay than parental cells. Our results suggest that p21 disruption preferentially sensitizes at least some cell types to DNA crosslinking agents.
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PMID:Cells lacking CIP1/WAF1 genes exhibit preferential sensitivity to cisplatin and nitrogen mustard. 917 48

Butyrate is a well known colonic luminal short chain fatty acid, which arrests cell growth and induces differentiation in various cell types. We examined the effect of butyrate on the expression of WAF1/Cip1, a potent inhibitor of cyclin-dependent kinases, and its relation to growth arrest in a p53-mutated human colon cancer cell line WiDr. Five millimolar butyrate completely inhibited the growth of WiDr and caused G1-phase arrest. WAF1/Cip1 mRNA was rapidly induced within 3 h by treatment with 5.0 mM butyrate, and drastic WAF1/Cip1 protein induction was detected. Using several mutant WAF1/Cip1 promoter fragments, we found that the butyrate-responsive elements are two Sp1 sites at -82 and -69 relative to the transcription start site. We also found that a TATA element at -46 and two overlapping consensus Sp1 sites at -60 and -55 are essential for the basal promoter activity of WAF1/Cip1. These findings suggest that butyrate arrests the growth of WiDr by activating the WAF1/Cip1 promoter through specific Sp1 sites in a p53-independent fashion.
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PMID:Butyrate activates the WAF1/Cip1 gene promoter through Sp1 sites in a p53-negative human colon cancer cell line. 926 65

We examined the effect of butyrate on the expression of WAF1, a potent inhibitor of cyclin-dependent kinases, and its relation to growth arrest in a p53-mutated human colon cancer cell line WiDr. Five millimolar butyrate completely inhibited the growth of WiDr and caused G1-phase arrest. WAF1 mRNA was rapidly induced by treatment with 5.0 mM butyrate, and significant WAF1 protein induction was detected. Using several mutant WAF1 promoter fragments, we found that the butyrate responsive elements are specific Sp1 sites. These findings suggest that butyrate arrests the growth of WiDr by activating the WAF1 promoter through specific Sp1 sites in a p53-independent fashion. Based on our results, we propose a novel approach for cancer chemoprevention, which we term "gene-regulating chemoprevention". Our strategy is to activate the potent function of growth-inhibitory genes, which are preserved in cancer cells. WAF1 is a good candidate, because it rarely appears to be mutated in common human tumors, while the p53 gene is frequently mutated. Therefore the p53-independent activation of WAF1 by butyrate could be applied to the prevention of cancer when p53 is mutated.
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PMID:[A novel approach for cancer chemoprevention referred to as "gene-regulating chemoprevention"]. 969 75

We have introduced an inducible wild-type p53 allele into the human SW480 colon cancer cell line, which bears an endogenous mutant p53 allele. The expression of inducible wild-type p53 is under basal repression by the lac repressor and is induced by isopropyl-beta-thiogalactopyranoside. The addition of isopropyl-beta-thiogalactopyranoside induces expression of wild-type p53 transcript and protein at a level no greater than that of the endogenous mutant p53. This level of wild-type p53 induction is sufficient both to induce expression of WAF1/CIP1 and to induce G1 cell cycle arrest. This p53-induced growth arrest is reversible after 6 days of continuous p53 expression, indicating that apoptosis is not induced. These results demonstrate that in a human colon epithelial cell background, wild-type p53 is functionally dominant over this mutant p53 and thus provides a mechanism for the observed inactivation of both copies of the p53 gene in most colon cancers. Moreover, despite the well-documented role of apoptosis in maintaining homeostasis in the nontransformed colon epithelium, these results demonstrate that restoration of wild-type p53 expression is insufficient to trigger apoptosis of transformed colonic cells.
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PMID:Wild-type p53 demonstrates functional dominance in a human colon carcinoma cell line in which it induces reversible growth arrest. 981 11

p53 tumor suppression is deficient in the majority of human cancers. Efforts to understand this pathway have identified cyclin-dependent kinase (CDK) inhibitors and suggested a potential for their replacement in human cancer. In the present studies, expression of a C-terminal deletion mutant of the human p21(WAF1/CIP1) CDK inhibitor completely suppressed the growth of colon cancer cells, whereas full-length p21 only partially suppressed growth. We prepared a replication-deficient adenoviral recombinant which expresses the p21 C-terminal mutant (Ad-WAF1-341) and compared its tumor suppressive abilities with Ad-p53 and Ad-LacZ. Ad-WAF1-341- and Ad-p53-infected cancer cells, but not Ad-LacZ-infected cancer cells, expressed a nuclear protein recognized by anti-p21 antibody and were deficient in cell cycle progression. The exogenous p21 mutant interacted with CDK2 but not proliferating cell nuclear antigen following infection of p21-/- cancer cells. Ad-WAF1-341 was more potent than Ad-p53 in inhibiting DNA synthesis in human papillomavirus 16 E6-expressing cancer cells. Most importantly, the Ad-WAF1-341-infected E6-expressing cells died, whereas most of the Ad-p53-infected cells continued to proliferate. Endonucleolytic cleavage of DNA was observed in Ad-WAF1-341-infected cancer cells. These observations suggest that Ad-WAF1-341 should be evaluated in the treatment of human papillomavirus-associated neoplasia and other neoplasias resistant to p53.
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PMID:Suppression of cancer cell growth by adenovirus expressing p21(WAF1/CIP1) deficient in PCNA interaction. 981 91

Inactivation of the p53 tumor suppressor protein has been observed in a large number of human cancers. Overexpression of p53 induces either growth arrest or programmed cell death (apoptosis). The growth arrest function of p53 is mediated by induction of p21 (WAF1/CIP1), but the mechanisms underlying p53-dependent apoptosis are still largely unknown. To investigate these mechanisms, we have identified six differentially expressed transcripts in a human colon cancer cell line undergoing p53-dependent apoptosis. One of the p53-responsive genes showed significant homology to Drosophila peroxidasin, an extracellular matrix-associated peroxidase, and is likely to be its human homologue. Our results suggest a possible connection between p53-dependent apoptosis and the production of reactive oxygen species.
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PMID:Isolation of differentially expressed cDNAs from p53-dependent apoptotic cells: activation of the human homologue of the Drosophila peroxidasin gene. 1044 17


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