Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Observations support the theory that development of left- and right-sided colorectal cancers may involve different mechanisms. This study investigated different genes involved in oncogenesis of colon and rectal cancers and analysed their prognostic value. The study group comprised 35 colon and 42 rectal cancers. Rectal cancer patients had been treated with standardized surgery performed by an experienced rectal cancer surgeon. Mutation analysis was performed for p53 in eight colon cancers and for APC and p53 in 22 rectal cancers. MLH1, MSH2, Bcl-2, p53, E-cadherin and beta-catenin were investigated by immunohistochemistry in all colorectal tumours. APC mutation analysis of the MCR showed truncating mutations in 18 of 22 rectal tumours (82%), but the presence of an APC mutation was not related to nuclear beta-catenin expression (p=0.75). Rectal cancers showed significantly more nuclear beta-catenin than colon cancers (65% versus 40%, p=0.04). p53 mutation analysis corresponded well with p53 immunohistochemistry (p<0.001). Rectal cancers showed significantly more immunohistochemical expression of p53 than colon cancers (64% versus 29%, p=0.003). In rectal cancers, a significant correlation was found between positive p53 expression and worse disease-free survival (p=0.008), but not in colon cancers. Cox regression showed that p53-expression (p=0.03) was an independent predictor for disease-free survival in rectal cancers. This study concluded that rectal cancer may involve more nuclear beta-catenin in the APC/beta-catenin pathway than colon cancer and/or nuclear beta-catenin may have another role in rectal cancer independently of APC. The p53-pathway seems to be more important in rectal cancer, in which it also has independent prognostic value. When prognostic markers are investigated in larger series, differences in biological behaviour between colon and rectal cancer should be considered.
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PMID:Mechanisms of oncogenesis in colon versus rectal cancer. 1159 95

High intakes of dietary fiber or resistant starches have been associated with a lower incidence of colon cancers. Because short-chain fatty acids (SCFA) such as butyrate are produced in the colonic lumen by the bacterial fermentation of dietary fibers and resistant starches, we hypothesized that SCFA may inhibit the development of invasive human colon cancers. To test this hypothesis, primary human invasive colonocytes were isolated from fresh surgical specimens and treated with 0.01 mol/L acetate, propionate or butyrate; cell invasion, cell adhesion, F-actin polymerization, urokinase plasminogen activator (uPA), tissue inhibitor matrix metalloproteinase (TIMP)-1, TIMP-2 and mutant p53, Bcl-2, Bax, p21 and proliferating cell nuclear antigen (PCNA) protein expression levels were examined. Although each of the SCFA tested significantly reduced primary cell invasion, butyrate was the most potent, inhibiting primary invasive human colon cancer invasion by 54% (P < 0.0001). The effects of SCFA on primary cell invasion appeared to be independent of cell adhesion and F-actin polymerization but dependent on the inhibition of uPA (P < 0.05) and the stimulation of TIMP-1 and TIMP-2 activities (P < 0.05). Protein expression levels of mutant p53, p21, Bax, Bcl-2 and PCNA were significantly altered by each of the SCFA tested (P < 0.05). These data indicate that SCFA inhibit invasive human colon cancer by modulating proteolytic uPA and antiproteolytic TIMP-1 and TIMP-2 activities, but their mechanisms of action on tumor suppression, apoptosis and growth arrest may differ.
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PMID:Short-chain fatty acids inhibit invasive human colon cancer by modulating uPA, TIMP-1, TIMP-2, mutant p53, Bcl-2, Bax, p21 and PCNA protein expression in an in vitro cell culture model. 1169 45

Although overexpression of E2F-1 can induce apoptosis in a variety of tumor cell lines, the mechanisms by which E2F-1 induces apoptosis remain ambiguous. In this study, we examine the ability of E2F-1 to induce apoptosis in colon cancer and the molecular mechanisms underlying E2F-1-mediated apoptosis. HT-29 and SW-620 colon adenocarcinoma cells (both mutant p53) were treated by mock infection or adenoviral vectors Ad5CMV (empty vector), Ad5CMVLacZ (beta-galactosidase), and Ad5CMVE2F-1 (E2F-1) at multiplicity of infection of 100. Western blot analysis confirmed marked overexpression of E2F-1 in both cell lines. By 5 days after infection, E2F-1 overexpression resulted in >25-fold reduction in cell growth and >90% loss of cell viability in both cell lines. Cell cycle analysis of Ad-E2F-1-infected cells revealed an increase in G(2)/M and sub-G(1) populations. By in situ terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling analysis, evidence of apoptosis was observed including internucleosomal DNA fragmentation and the formation of apoptotic bodies. In addition, caspase-3 and poly(ADP-ribose) polymerase apoptotic fragments were detected by 48 h after treatment with Ad-E2F-1. Of mechanistic importance, overexpression of E2F-1 caused a G(2)/M arrest followed by increased levels of c-Myc and p14(ARF) proteins. Additionally, expression of the antiapoptotic Bcl-2 family member Mcl-1 was down-regulated in E2F-1-overexpressing cells. In conclusion, E2F-1 overexpression initiates apoptosis and suppresses growth in HT-29 and SW620 colon adenocarcinoma cells. Overexpression of E2F-1 triggers apoptosis and is associated with up-regulation of c-Myc and p14(ARF) proteins and down-regulation of Mcl-1. Therefore, E2F-1 is a potentially active gene therapy agent for the treatment of colon cancer.
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PMID:E2F-1 up-regulates c-Myc and p14(ARF) and induces apoptosis in colon cancer cells. 1170 81

Epidemiological and preclinical studies demonstrate that consumption of diets high in omega-3 fatty acids (n-3 PUFAs) reduce the risk of colon cancer. Docosahexaenoic acid (DHA), a long chain polyunsaturated fatty acid (PUFAs) is a major constituent of nutrients rich in n-3 PUFAs. There are studies to indicate that colon tumor inhibition by n-3 PUFA-rich diets is, in part, mediated through modulation of signaling pathways that alter gene expression which are involved in colon tumor growth. In the present study using CaCo-2 colon cancer cell lines we examined the effects of DHA on the genetic precursors of human colon cancer at the transcription level using DNA oligonucleotide arrays. Our results indicated that DHA inhibits the growth of CaCo-2 cells and induces apoptosis. For gene expression analysis using DNA microarrays, total RNA extracted from DHA treated CaCo-2 cells was converted to cDNA, labeled with Cy5-dCTP (DHA-treated) and Cy3-dCTP (untreated cells) and used as probes for hybridization in human chip spotted with 3,800 oligonucleotides consisting of 156 functional categories. The expression profiles of genes indicated a reprogramming pattern of previously known and unknown genes and transcription factors that provided clues to the possible functional mechanism of DHA. An average of (ratios from triplicate experiments) 504 out of 3,800 genes expressed after 48 h of DHA treatment. Altered expression on the transcription factors includes down regulation of nine members of the RNA II polymerases, transcription co-repressor associated protein and enhancer binding proteins such as AP2, in addition to changes in the expression of zinc finger group of transcription factors. Activation of cytochrome c which triggers caspases was associated with the elevated expression of pro-apoptotic caspases 10, 13, 8, 5 and 9 in DHA treated cells. Activation of cyclin-dependent kinase inhibitors such as p21 (waf1/cip1), p27, p57, p19 and growth arrest specific proteins by more than 2-fold is consistent with the induction of apoptosis and inactivation of antiapototic Bcl-2 family of genes. Inactivation of prostaglandin family of genes, lipoxygenases and altered expression of peroxisome proliferators (PPARalpha and gamma) by DHA seem to indicate a lipid peroxidation-induced apoptosis in addition to effect reflected on the modification of cell cycle regulatory genes. These findings support the conclusion that a genomewide expression profiling of human colon cancer precursor genes and transcription factors provides a set of novel regulatory mechanism(s) to determine the chemopreventive efficacy of DHA and thus to prevent the inflammation and neoplasia.
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PMID:Docosahexaenoic acid regulated genes and transcription factors inducing apoptosis in human colon cancer cells. 1171 97

Interleukin 15 (IL-15 mRNA expression was detected in human colorectal cancer cells (Colo320, WiDr, TCO and DLD1) by the reverse transcriptase-polymerase chain reaction (RT-PCR). Only Colo320 and WiDr cells secreted IL-15 culture medium. With IL-15 treatment, all cell lines grew at a rate of 120-180% of that of nontreated cells. A binding assay with (125)I-labeled IL-15 showed binding activity to IL-15 in Colo320 (K(d): 0.098 nM) cells. IL-15 also reversed the growth inhibition caused by serum starvation in Colo320 cells. IL-15-induced cell growth in regular and serum-free media was abrogated by anti-IL-15 antibody treatment in Colo320 cells. Moreover, IL-15 treatment reduced doxorubicin-induced cytostasis and cytolysis in Colo320 cells by 50%. The invasion capacity of IL-15-treated Colo320 cells was 5.3 times that of untreated cells. Immunoblotting showed that IL-15-treated Colo320 cells exhibited downregulation of p21Waf1 and Bax, and upregulation of Bcl-2, phospho-AKT, MMP9/MMP2, and VEGF. Finally, immunostaining of human colon cancer revealed that 33 (70%) of 47 Dukes' C cases showed IL-15 expression in cancer cells, whereas only 16% of Dukes' B cases did (p < 0.0001). IL-15 may play important roles in cell proliferation, invasion, and metastasis of human colorectal cancer.
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PMID:Interleukin-15 expression is associated with malignant potential in colon cancer cells. 1175 2

Although the pharmacological role of beta-carotene in the prevention and treatment of colon cancer has received increasing attention, little is known about the molecular mechanisms of action of this carotenoid. The present study demonstrates that beta-carotene, a natural pigment widely present in fruit and vegetables, inhibits the growth of several human colon adenocarcinoma cell lines (COLO 320 HSR, LS-174, HT-29 and WiDr) by inducing cell cycle arrest in G(2)/M phase and apoptosis. These effects were dose and time dependent and strictly related to cell ability to accumulate the carotenoid. COLO 320 HSR cells incorporated beta-carotene to a greater extent than LS-174, HT-29 and WiDr cells and, concomitantly, they exhibited a higher sensitivity to the growth inhibitory effects of the carotenoid. At inhibitory concentrations beta-carotene reduced the expression of cyclin A, a key regulator of G(2)/M progression. Neither p21 nor p27, two cyclin kinase inhibitors, were significantly modified by carotenoid treatment. With respect to apoptosis induction, decreased levels of the apoptosis blocking proteins Bcl-2 and Bcl-xL were also observed. On the other hand, no changes in expression of the apoptosis promoter protein Bax were detected. This study represents a novel aspect of the biological profile of beta-carotene and a new step in elucidating the underlying molecular mechanisms of its antitumor action. In addition, since cell growth inhibitory effects were reached at beta-carotene concentrations achievable in vivo following its supplementation, this study provides a rational approach for the use of beta-carotene in colon cancer.
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PMID:Induction of cell cycle arrest and apoptosis in human colon adenocarcinoma cell lines by beta-carotene through down-regulation of cyclin A and Bcl-2 family proteins. 1175 18

Defects in apoptosis have been implicated in chemoresistance of colon cancer cells. We report here the ability to resist to 5-fluorouracil-induced apoptosis of 8 colon cancer cell lines differing in p53 and bax status: p53(-/0)bax(+/+) for TC7, SW480, HT-29; p53(+/+)bax(-/-) for LS174T, LoVo; p53(+/+) bax(+/-) for HCT116; p53(+/+) or p53(+/0)bax(+/+) for LS513 or HCT-EB, respectively. To approximate to the in vivo therapy, the cell lines were exposed to a long-term treatment of 5-FU. The analysis of proteins implicated in the apoptotic pathway has shown that the independent analysis of p53 or bax status was not sufficient to predict the extent of drug-resistance of all cell lines. In p53(+/+) cell lines but not in p53(-/0) cell lines, a low level of the pro-apoptotic Bax protein was correlated with a greater resistance of cells to 5-FU. In addition, we found that high levels of anti-apoptotic Bcl-2 and Bcl-x(L) proteins combined with a low level of Bax were correlated to high 5-FU resistance of wild-type p53 cell lines. The same correlation was obtained for 2 out of 3 mutated p53 cell lines. In conclusion, the relative levels of Bcl-2, Bcl-x(L) and Bax may altogether contribute to determine the resistance of a majority of colon tumor cells to long-term 5-FU treatment, whatever their p53 status.
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PMID:Resistance of colon cancer cells to long-term 5-fluorouracil exposure is correlated to the relative level of Bcl-2 and Bcl-X(L) in addition to Bax and p53 status. 1192 Jun 8

Exposure of three colon cancer cell lines, SW480, DLD-1, and COLO201, to arsenic trioxide in the medium induced a marked concentration-dependent suppression of cell growth. The intracellular contents of reduced glutathione (GSH) in these cell lines tended to be inversely correlated with the sensitivity of the cells to arsenic trioxide. Among the cell lines, SW480 cells underwent apoptosis at the low arsenic trioxide concentration of 2 microM, which was prevented by pretreatment of the cells with N-acetylcysteine and was enhanced by buthionine sulfoximine. The production of reactive oxygen intermediates which were examined by 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA), increased with time after treatment with arsenic trioxide. The apoptosis was executed by the activation of caspase 3, which was shown by Western blot, enzymatic activity, and apoptosis inhibition assay. The mitochondrial membrane potential of adherent apoptotic SW480 cells and the cells from intermediate layer separated by density gradient centrifugation, both of which showed the active form of caspase 3 by Western blot analysis, was not lost. The overexpression of Bcl-2 protein in SW480 cells could not prevent the apoptosis induced by the treatment with arsenic trioxide. All these findings indicate that arsenic trioxide-induced apoptosis in SW480 cells is executed by the activation of caspase 3 without mediating by mitochondria under the overproduction of reactive oxygen species.
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PMID:Arsenic trioxide-induced apoptosis through oxidative stress in cells of colon cancer cell lines. 1200 85

The human INK4a gene locus encodes two structurally unrelated tumor suppressor proteins, p16(INK4a) and p14(ARF), which are frequently inactivated in human cancer. Whereas p16(INK4a) acts through engagement of the Rb-cdk4/6-cyclin D pathway, both the pro-apoptotic and cell cycle-regulatory functions of p14(ARF) were shown to be primarily dependent on the presence of functional p53. Recent reports have also implicated p14(ARF) in p53-independent mechanisms of cell cycle regulation and apoptosis induction, respectively. To further explore the pro-apoptotic function of p14(ARF) in relation to functional cellular p53, we constructed a replication-deficient adenoviral vector for overexpression of p14(ARF) (Ad-p14(ARF)). As expected, Ad-p14(ARF) efficiently induced apoptosis in p53/Rb wild-type U-2OS osteosarcoma cells at low multiplicities of infection. Interestingly, Ad-p14(ARF) also induced apoptosis in both p53-deleted SAOS-2 osteosarcoma cells and HCT116 colon cancer cells with a bi-allelic knock-out of p53 (HCT116-p53(-/-)). Similarly, adenovirus-mediated overexpression of p14(ARF) induced apoptosis in p53/Bax-mutated DU145 prostate cancer cells as well as in HCT116 cells devoid of functional Bax (HCT116-Bax(-/-)). Restoration of Bax expression by retroviral gene transfer in DU145 cells did not further enhance p14(ARF)-triggered cell death. Infection with Ad-p14(ARF) induced activation of mitochondrial permeability shift transition, caspase activation and apoptotic DNA fragmentation irrespective of the presence or absence of either Bax or functional cellular p53. Nevertheless, overexpression of the anti-apoptotic Bcl-2 homolog Bcl-x(L) markedly inhibited p14(ARF)-induced apoptosis. This may indicate that p14(ARF) triggers a so far unknown activator of mitochondrial apoptosis which can be inhibited by Bcl-2 but which acts either independently or downstream of Bax. Taken together, this report demonstrates the participation of signaling pathways apart from the p53/Mdm-2 rheostat and Bax in p14(ARF)-mediated apoptosis.
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PMID:Adenovirus-mediated overexpression of p14(ARF) induces p53 and Bax-independent apoptosis. 1208 30

We studied the molecular events underlying butyrate-induced apoptosis in two different colon cancer cell lines: Caco-2, a well defined cancer cell and RSB, a cell line obtained from a colonic tumor of an ulcerative colitis patient. Caco-2 and RSB cells were exposed to 2, 5 and 10 mmol/L butyrate for 48 h. Caspase-1 was cleaved in Caco-2-cells at all butyrate concentrations, whereas in RSB-cells caspase-1 expression was undetectable. In RSB cells, butyrate dose-dependently induced caspase-3 cleavage, whereas in Caco-2-cells, butyrate up-regulated expression of the caspase-3 active subunit. Caspase-3-specific activity, cytoplasmic nucleosome concentration and growth were directly correlated with butyrate doses in both cell lines; however, the response was more pronounced in Caco-2 than in RSB cells. Expression of the cleaved poly(ADP-ribose) polymerase (PARP) product was elevated in both cell lines at the highest butyrate concentration. Bak expression gradually increased as a function of butyrate concentrations in both cell lines. At 10 mmol/L butyrate, expression increased by fivefold and sevenfold in Caco-2 and RSB cells, respectively. The highest expression of Bcl-2 was observed in control Caco-2 cells, and expression decreased with increasing butyrate concentration. This effect was not observed in RSB cells. Inactivation of caspase-1 with Z-YVAD-FMK abrogated butyrate-induced apoptosis in Caco-2 but not in RSB cells. Inactivation of caspase-3 with Z-DVED-FMK completely inhibited butyrate-induced apoptosis in RSB cells whereas this effect was less pronounced in Caco-2 cells. Our data demonstrate that butyrate-induced apoptosis is activated via different apoptotic pathways in diversely stratified colon cancers.
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PMID:Different molecular events account for butyrate-induced apoptosis in two human colon cancer cell lines. 1209 52


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