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)

Modulation of apoptosis may influence resistance to chemotherapy and therefore affect the outcome of cancer treatment. Ovarian cancer, one of the most fatal malignancies in women, is often associated with drug resistance but the cellular pathways contributing to this effect remain obscure. We have found that Bcl-2 and p53, two proteins implicated in the control of apoptosis, are frequently expressed in fresh biopsies of primary ovarian carcinoma. Examination of Bcl-2 and p53 protein levels in pairs of cis-platin sensitive and resistant ovarian cell lines demonstrated that the resistant variants over-express Bcl-2 and/or p53, apparently due to progressive expansion of Bcl-2 and/or p53 positive subpopulations during the in vitro development of resistance. Exogenous expression of Bcl-2 or a temperature sensitive mutant p53 (ts p53) in the ovarian cell line A2780 resulted in protection from drug-induced apoptosis and a delay in drug-mediated S-phase arrest. Interestingly, p53 accumulation in response to DNA damage induced by different agents was significantly delayed and reduced in the Bcl-2 transfectants compared to the control A2780 line, suggesting that Bcl-2 may act upstream of the p53 pathway. Similarly, the induction of Bax mRNA and protein was also found to be delayed in the presence of Bcl-2. Overall, our data provide further evidence for cross-talk between Bcl-2, p53 and Bax and suggest that these genes are important determinants of drug-induced apoptosis thereby modulating resistance to chemotherapy.
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PMID:The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and Bcl-2. 747 41

We investigated the roles of p53 and Bcl-2 homologues in the induction of apoptosis by cisplatin and paclitaxel in wild-type p53-expressing human ovarian carcinoma cells and cisplatin-resistant derivatives that have lost p53 function. Cisplatin induced apoptosis in parental A2780 but not in cisplatin-resistant A2780/cp70 cells, whereas paclitaxel induced apoptosis in both cell lines. Immunoprecipitation of p53 using antibodies specific for p53 conformation (pAb 1620 and pAb 240) showed that there were no relative changes in p53 conformation before and after cisplatin treatment in either cell line. A2780/cp70 cells have lost p53 function, yet they have wild-type p53 gene sequence. However, A2780/cp70 cells constitutively express more p53 in a form detected by pAb 240, an antibody that also detects mutant conformations of p53 that are transcriptionally inactive. There were no changes in levels of Bcl-2, Bcl-XL, or 24-kDa Bax over 72 hr after exposure to cisplatin or paclitaxel, but each agent led to up-regulation of Bak and 21-kDa Bax in A2780 cells. Paclitaxel, but not cisplatin, increased Bak and 21-kDa Bax levels in A2780/cp70 cells. These data suggest that apoptosis in A2780 and A2780/cp70 is associated with an increased level of Bak and 21 kDa Bax after drug-induced damage and that functional p53 may be required for this effect after cisplatin but not after paclitaxel.
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PMID:Cisplatin- and paclitaxel-induced apoptosis of ovarian carcinoma cells and the relationship between bax and bak up-regulation and the functional status of p53. 958 7

A panel of 16 human ovarian carcinoma cell lines comprising cisplatin naive as well as those with acquired cisplatin resistance was studied to determine if there was a relationship between ras status and cisplatin sensitivity. From the ras expression studies alongside data produced by direct DNA sequencing, there was very little to suggest that ras overexpression or mutation plays a role in the cisplatin sensitivity of the panel of human ovarian carcinoma cell lines tested. A weak correlation (r2 = 0.53) was found between total Ras protein levels and resistance to cisplatin. No relationship was found between Kirsten-Ras protein levels and cisplatin sensitivity (r2 = 0.0). Only one ras mutation (codon 13, Kirsten exon 1, glycine --> aspartate in the HX62 cell line) was observed in the cisplatin naive cell lines from the panel which comprised both cisplatin sensitive and resistant models. Of interest, however, was that the HX62 cell line was the most resistant to cisplatin. No ras mutations were found in those cell lines which had repeatedly been exposed, and acquired resistance, to cisplatin. The A2780 and CH1 human ovarian carcinoma cell lines were transfected with activated, mutant Harvey-ras and, as a result, were shown to display elevated MAP kinase phosphorylation in low serum concentration growth medium. No changes in cisplatin sensitivity were found following transfection with activated Harvey-ras in these 2 human ovarian carcinoma tumor cell models which, importantly, differed greatly in their expression of Bcl-2. Therefore, when conducted under similar conditions to previously published studies, very little evidence was found to support Harvey-ras activation as a factor which can either sensitize or confer resistance to cisplatin in human ovarian carcinoma cell lines.
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PMID:ras mutation and platinum resistance in human ovarian carcinomas in vitro. 963 99

The oncogenic protein Bcl-2 functions as a potent inhibitor of programmed cell death. This survival activity has been shown in some settings to be influenced by the Bcl-2 phosphorylation state. It has been demonstrated that treatment with microtubule-targeted agents results in phosphorylation of both Raf-1 kinase and Bcl-2. The Bcl-2-related family member Bcl-xL also exhibits a death suppressive activity, but its potential for phosphorylation following exposure to drugs that interact with microtubules has not been evaluated. Several tumor cell lines with low or undetectable levels of Bcl-2 protein expression were found to express Bcl-xL. A more slowly migrating Bcl-xL band was observed on immunoblots after cells were treated with microtubule-targeted agents. The appearance of this band was responsive to dose and was absent when the cell lysates were treated with lambda protein phosphatase. Using a Bcl-xL-specific monoclonal antibody, the phosphorylated form of Bcl-xL was immunoprecipitated from cells treated with paclitaxel and metabolically labeled with 32P-labeled inorganic orthophosphate. Herein, we report that Bcl-xL is phosphorylated in malignant cells after incubation with agents that target tubulin, including paclitaxel, vincristine, vinblastine, colchicine, and nocodazole. Moreover, paclitaxel-resistant ovarian carcinoma cell lines that have mutations in tubulin failed to exhibit phosphorylation of Bcl-xL after paclitaxel exposure, but they did demonstrate Bcl-xL phosphorylation in the presence of other tubulin-targeting agents. As observed for Bcl-2, phosphorylation of Bcl-xL was accompanied by phosphorylation of Raf-1. Interestingly, phosphorylation of these three proteins failed to occur or was much less pronounced when cells grown at high density were challenged with drug. Also, reduced Raf-1 expression, observed after treatment of cells with geldanamycin prior to and during incubation with the microtubule-active drugs, correlated with diminished Bcl-xL phosphorylation. Taken together, these results suggest that Bcl-xL, like Bcl-2, is phosphorylated by agents that disrupt microtubule architecture. By analogy with Bcl-2, this phosphorylation may play a critical role in modulating Bcl-xL function and may be an important determinant of microtubule-directed chemotherapeutic efficacy in human tumors.
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PMID:Bcl-xL is phosphorylated in malignant cells following microtubule disruption. 969 63

Our goal was to determine the cytotoxicity of 7-OH-hydroxystaurosporine (UCN-01) as a single agent and in combination with cis-diamminedichloroplatinum(II) (CDDP) in a panel of ovarian carcinoma cells. We sought to examine the role of p53 gene function and alterations in cell cycle progression or other mechanisms of action of UCN-01 including perturbation of the apoptosis pathway mediated by NF-kappaB and Bcl-2/Bax. Cytotoxicity was determined from dose-response curves established by the Alamar blue vital dye indicator assay. Restoration of wild-type p53 in a p53 null cell line, SKOV 3, was achieved by transfection of a p53 expression vector. Cell cycle distribution was measured by fluorescence-activated cell sorting analysis of ethidium bromide-stained nuclei. Apoptosis was measured by quantitative fluorescence microscopy. NF-kappaB DNA binding activity was measured by electrophoretic mobility shift assay. Bcl-2 and Bax levels were determined by Western immunoblotting. UCN-01 was effective as a cytotoxic agent alone and in combination with CDDP in all cell lines studied, regardless of p53 status. The degree of sensitization to CDDP conferred by UCN-01, however, was found to correlate with p53 gene status. p53 wild-type cells seem to be more sensitive to the cytotoxic effects of the combination of UCN-01 + CDDP than the p53 mutant cells. This was confirmed in cells in which p53 wild-type function was restored by transfection of p53 cDNA, but these cells are also significantly more sensitive to CDDP alone. The effects of UCN-01 on cell cycle progression also appear to be p53 dependent but may not be the primary mechanism of action. The rate of apoptosis is increased 4-fold in UCN-01 + CDDP-treated cells compared to either agent alone. UCN-01 does not effect NF-kappaB DNA binding activity or Bcl-2 and Bax levels. UCN-01 enhances CDDP cytotoxicity and apoptosis in ovary cancer cells. This occurs regardless of p53 status, but wild-type p53 seems to increase the degree of sensitization.
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PMID:UCN-01 in ovary cancer cells: effective as a single agent and in combination with cis-diamminedichloroplatinum(II)independent of p53 status. 981 1

p53 has been implicated as a determinant of chemosensitivity and radiosensitivity. We measured chemosensitivity of human tumor cell lines (n = 11), with or without wild-type p53, following exposure to clinically useful chemotherapeutic drugs (n = 4). Chemosensitivity and apoptosis induction were correlated independently of p53 status or Bcl-2 protein levels in vitro. Wild-type p53 correlated with chemosensitivity in ovarian carcinoma and some Burkitt's lymphoma cells, but not in leukemia or lung cancer. Bcl-2 levels correlated with chemoresistance only in Burkitt's lymphoma. p53-dependent p21(WAF1/CIP1) induction and cell cycle arrest occurred at sublethal doses of chemotherapy, whereas at lethal doses of chemotherapy apoptotic death was observed, consistent with models proposing a relationship between the level of DNA damage versus survival or death. Loss of apoptosis induction was observed in drug-resistant ML-1 and HL-60 leukemia cells, without changes in p53 or Bcl-2. Targeted loss of p53 protein in H460 lung cancer cells using HPV-16 E6 inhibited the etoposide-induced G1 checkpoint but did not decrease chemosensitivity. Our studies suggest that the simple measurement of apoptosis induction may be a useful predictor of chemosensitivity, at least in vitro, and confirm that p53 status and Bcl-2 expression may be useful predictors of chemosensitivity in certain cell types.
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PMID:Apoptotic death of tumor cells correlates with chemosensitivity, independent of p53 or bcl-2. 981 12

In a systematic study to elucidate the involvement of pro- and anti-apoptotic proteins in alkylating drug resistance of tumor cells, we utilized the A2780(100) line, that was selected by repeated exposure of A2780 cell line (human ovarian carcinoma line) to chlorambucil (CBL). A2780(100) was 5 - 10-fold more resistant to nitrogen mustards (IC50 of 50 - 60 microM) and other DNA crosslinking agents, e.g., cisplatin, and also to DNA topoisomerase inhibitor etoposide (ETO) than A2780. CBL (125 microM) induced extensive apoptosis in A2780 associated with mitochondrial damage but not in A2780(100). No significant differences were observed between A2780 and A2780(100) cells in the basal levels, or the enhanced levels in some cases after CBL treatment, of DNA repair proteins involved in repair of alkyl base adducts or in repair of DNA crosslinks or double strand break repair. However, the basal levels of anti-apoptotic proteins Bcl-xL and Mcl-1 were 4 - 8-fold higher in A2780(100) than in A2780 neither of which expressed Bcl-2. In contrast, the levels of pro-apoptotic Bax and Bak were 3 - 5-fold higher in the CBL-treated A2780 but not in A2780(100). ETO (5 microM) induced apoptosis in A2780 without altering the levels of Bax and Bak in these cells. At the same time, neither overexpression of Bcl-xL in A2780, nor its antisense expression in A2780(100), and nor overexpression of Bax in A2780(100), significantly affected drug sensitivity of either line. Our results suggest that a change in an early step in DNA damage processing which affects intracellular signaling, such as enhanced DNA double-strand break repair, could be the primary cause for development of resistance in A2780(100) cells to drugs which induce DNA crosslinks or double strand-breaks.
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PMID:Acquired alkylating drug resistance of a human ovarian carcinoma cell line is unaffected by altered levels of pro- and anti-apoptotic proteins. 1064 89

Bcl-2 is a proto-oncogene which is involved in prolonging cell survival by inhibiting programmed cell death. Bax and bcl-x are members of the bcl-2 family; when overexpressed, they can counteract the ability of bcl-2 to inhibit apoptosis. This suggests a model in which the ratios of bcl-2 to bax and bcl-x can be used to determine response to therapy and prognosis. The expression of bcl-2, bax and bcl-x was studied in 50 ovarian carcinomas. The percentage of positive area immunostained (PPA) in the nucleus and cytoplasm of each ovarian carcinoma was quantitated in 15 high power fields by image cytometry. The ratios were obtained by dividing the PPA of bcl-2 by the PPA of bax and bcl-x. 17 of 50 ovarian carcinomas (34%) stained positively for bcl-2, 39 for bax (78%) and 47 for bcl-x (94%). Although there is no significant statistical correlation between expression of bcl-2, bax or bcl-x and grade (P = 0.15; P = 0. 47; P = 0.56), stage (P = 0.71; P = 0.6; P = 0.42), and overall or disease-free survival (P = 0.26; P = 0.55; P = 0.16), increased bcl-2 expression was demonstrated in patients with shortened overall and disease-free survival. Also, increased expression of bax and bcl-x was associated with increased overall and disease-free survival. Bcl-2:bax and bcl-2:bcl-x ratios less than 1 are associated with survival advantage, although not statistically significant (P = 0.83; P = 0.93). Image cytometric measurement of bcl-2, bax, and bcl-x expression is feasible. There is a tendency for their expression to correlate with prognosis in ovarian carcinomas.
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PMID:Bcl-2: bax and bcl-2: Bcl-x ratios by image cytometric quantitation of immunohistochemical expression in ovarian carcinoma: correlation with prognosis. 1067 44

In the present study, we investigated the radiosensitivity profiles of three established human ovarian carcinoma cell lines, PA-1, Caov-3, and SK-OV-3, using the adenosine triphosphate-cell viability assay (ATP-CVA). We have correlated radioresponsiveness with the p53 status and the p53 accumulation after irradiation as well as with the Bcl-2 expression and the growth rate of these cell lines. The p53 status was examined by immunocytochemistry and a functional assay (functional analysis of separated alleles in yeast, FASAY); the p53 accumulation was determined by immunocytochemistry and flow cytometry. Furthermore, the Bcl-2 expression before and after irradiation was examined by immunocytochemistry. PA-1, expressing wild-type p53, showed an unequivocal accumulation of p53 protein following exposure to irradiation. This cell line was found to be strongly sensitive to irradiation. The two p53 mutant cell lines Caov-3 and SK-OV-3 showed radioresistance at different degrees and irradiation did not result in p53 accumulation. None of the cell lines examined expressed Bcl-2 protein and no change was seen after irradiation. Furthermore, the most sensitive cell line to irradiation, PA-1, showed the highest proliferative activity, while Caov-3 and SK-OV-3, the more resistant cell lines, exhibited lower growth rates. Our findings indicate that the presence of p53 protein is a possible determinant for the cytotoxicity induced by irradiation in the investigated ovarian carcinoma cell lines. Bcl-2 expression does not seem to determine the response to irradiation in these cell lines. Additionally, an association between radioresponsiveness and the growth rate is suggested in PA-1, Caov-3, and SK-OV-3.
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PMID:p53-dependent radioresistance in ovarian carcinoma cell lines. 1070 42

Papillary serous carcinoma of the peritoneum (PSCP) is believed to develop de novo from the peritoneal lining of the pelvis and abdomen. Although it is histologically indistinguishable from serous ovarian carcinoma, PSCP exhibits minimal or absent ovarian involvement and may even develop in a woman years after prophylactic oophorectomy. We have shown previously that patients with germ-line BRCA1 mutations who develop PSCP are more likely to have disease originating from multiple peritoneal sites compared with patients with wild-type BRCA1. In this study, we tested the hypothesis that BRCA1-related PSCP has a unique molecular pathogenesis. DNA was extracted from normal tissue and multiple tumor sites in patients with PSCP. BRCA1 and p53 gene mutations were screened for using single-strand conformation polymorphism. Loss of heterozygosity was determined at the BRCA1 and p53 loci. Immunohistochemical analyses of p53, epidermal growth factor receptor, erbB-2, erbB-3, erbB-4, and Bcl-2 expression were performed. We detected germ-line BRCA1 mutations in 11 (26%) of 43 PSCP patients. BRCA1 mutation carriers had a higher overall incidence of p53 mutations (89% versus 47%; P = 0.052), were more likely to exhibit multifocal or null p53 mutations (63% versus 7%; P = 0.014), and were less likely to exhibit erbB-2 overexpression (P = 0.013) than wild-type BRCA1 case subjects. We propose that the unique molecular pathogenesis of BRCA1-related PSCP may affect the ability of current methods to reliably prevent or detect this disease prior to metastasis.
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PMID:BRCA1-related papillary serous carcinoma of the peritoneum has a unique molecular pathogenesis. 1072 99


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