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)

Studies of the mechanism of actions of estrogen, antiestrogen and physical factors may provide clues to an understanding of breast cancer growth and/or regression regulation and thus identify novel targets for therapeutic intervention. Defective control of apoptosis appears to play a central role in the pathogenesis of neoplasia. Conversely, cancer therapy and ionizing radiation can induce cancer cell death by apoptosis and/or necrosis. bcl-2 gene and p-53 gene products have been both linked to programmed cell death pathways. We have analyzed the effect of estradiol, tamoxifen and UV exposure on the induction of apoptosis, expression of p53 and bcl-2 gene products as well as the proliferative activity (expressed as [3H]thymidine incorporation and PCNA and MPM2 antigens involvement) in MCF7. It has been found that estradiol increases the speed of cell cycle in MCF7 and acts as antiapoptotic factor. Tamoxifen has multiple influence on the rate of growth of cancer cells: depends on estrogen receptor (ER), conducts reduction of proliferation rate; depends on ER and other mechanisms conducts to suppressions of Bcl-2 protein expression and induction of cell death through apoptotic pathway. Estradiol prevents the apoptotic influence of tamoxifen probably by enhancement of Bcl-2 protein expression and does not prevent the inhibition of proliferation rate. The irradiation with UV induces apoptosis by over-expression of p53 and down-regulation of bcl-2 gene.
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PMID:Influence of estrogen, antiestrogen and UV-light on the balance between proliferation and apoptosis in MCF-7 breast adenocarcinoma cells culture. 1087 Jun 82

Heat shock protein 70 is an antiapoptotic chaperone protein highly expressed in human breast tumors and tumor cell lines. Here, we demonstrate that the mere inhibition of its synthesis by adenoviral transfer or classical transfection of antisense Hsp70 cDNA (asHsp70) results in massive death of human breast cancer cells (MDA-MB-468, MCF-7, BT-549, and SK-BR-3), whereas the survival of nontumorigenic breast epithelial cells (HBL-100) or fibroblasts (WI-38) is not affected. Despite the apoptotic morphology as judged by electron microscopy, the asHsp70-induced death was independent of known caspases and the p53 tumor suppressor protein. Furthermore, Bcl-2 and Bcl-X(L), which protect tumor cells from most forms of apoptosis, failed to rescue breast cancer cells from asHsp70-induced death. These results show that tumorigenic breast cancer cells depend on the constitutive high expression of Hsp70 to suppress a transformation-associated death program. Neutralization of Hsp70 may open new possibilities for treatment of cancers that have acquired resistance to therapies activating the classical apoptosis pathway.
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PMID:Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2. 1088 17

We have established a Noble rat model to explore the mechanisms of hormonal mammary carcinogenesis, in which the role of androgen in promoting mammary carcinogenesis was highlighted. We have also established that stromal-epithelial interactions may be responsible for the promotional effects of testosterone in mammary carcinogenesis. Based on these understandings, in the present study we examined the expression of Bcl-2 and Bax in pre-malignant mammary glands from rats treated with different protocols of sex hormones for 7 weeks as well as sex hormone induced mammary tumours. We observed that Bcl-2 was strongly expressed in most of mammary tumour cells, whereas weak or negative in adjacent normal or hyperplastic ductal structures. On the contrary, Bax immunoreactivity was weak in mammary tumour cells while strongly expressed in adjacent normal or hyperplastic ductal structures. More importantly, the results from comparative study of 'pre-malignant' glands further showed that when animals were treated with 17beta-oestradiol, the mammary epithelial cells expressed high levels of Bcl-2. The results from rats treated with testosterone, either alone or in combination with oestrogen, give rise to high levels of Bax expression in 'pre-malignant' mammary glands. These observations indicate that in 'pre-malignant' mammary glands, treatment with testosterone, either alone or in combination with 17beta-oestradiol, may induce high apoptotic activities. However, in fully developed mammary tumours, the apoptotic activities apparently decrease in tumour cells. TUNEL assay provides further data to support this conclusion. Our study, thus, suggests that androgens may play a promoting role in mammary carcinogenesis by upregulation of Bax expression and induction of high apoptotic activities in 'pre-malignant' stage, which would provide a selective pressure favouring the expansion of the initiated cells.
Breast Cancer Res Treat 2000 May
PMID:Sex hormone-induced mammary carcinogenesis in the female Noble rats: expression of bcl-2 and bax in hormonal mammary carcinogenesis. 1093 89

Aberrant function of redox-regulated proteins is a possible cause for cellular transformation and loss of cell cycle control. The small protein thioredoxin has oncogenic properties and controls cell cycle movement through G(1), S, and G(2)/M phases. The redox-active, asymmetrical 1-methylpropyl-2-imidazolyl disulfide (IV-2) has previously been shown to react with and inhibit thioredoxin activity in vitro, the proliferation of human tumor cells in culture, and the growth of tumors in mice. We now examined the effects of IV-2 on cell cycle progression. In synchronized tsFT210 mouse mammary carcinoma cells, IV-2 halted cells in mitosis. In asynchronously growing MCF-7 human breast cancer cells, IV-2 exclusively and irreversibly blocked cells in G(2)/M at concentrations that correlated with its growth inhibitory activity. Neither the closely related, less redox active 2-hydroxy-1-methylpropyl-2-imidazolyl disulfide (AIV-2), which differs from IV-2 only by an additional hydroxyl group, nor the symmetrical diallyl disulfide caused a G(2)/M arrest under these conditions. Furthermore, MCF-7 cells treated with IV-2 showed increased Cdk1 kinase activity and a decrease in Cdk1 tyrosine phosphorylation, indicating that IV-2 did not directly inhibit Cdk1 or Cdc25 activities. IV-2 did, however, increase Bcl-2 phosphorylation. These data suggest that the thioredoxin inhibitor IV-2, despite its simple structure, is able to target redox-sensitive processes that are critical for cell cycle progression through mitosis. The results are also consistent with a role of thioredoxin regulating cell cycle progression through G(2)/M.
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PMID:Antitumor imidazolyl disulfide IV-2 causes irreversible G(2)/M cell cycle arrest without hyperphosphorylation of cyclin-dependent kinase Cdk1. 1094 61

Programmed cell death is an important determinant of the response to chemotherapy. Among the factors controlling this process, a significant role is played by bcl-2, bax and p53. The in vitro chemosensitivity of the 177 breast carcinomas was assessed by the histoculture drug response assay (HDRA) using mitomycin C (MMC), 5-fluorouracil (5-Fu), adriamycin (ADM), cisplatin (CDDP), and cyclophosphamide (CPA). The susceptibility of Bcl-2-negative tumors to all the drugs killing was significantly higher than that of Bcl-2-positive tumors. No relationship between Bax or p53 immunoreactivity and sensitivity for any of anticancer drugs studied was demonstrated. Immunohistochemical results regarding Bcl-2 are promising in the evaluation of the sensitivity of cancer cells to a series of anticancer drugs and might be therapeutically useful as an indicator of response to adjuvant chemotherapy for breast cancer.
Breast Cancer Res Treat 2000 Jun
PMID:Expression of Bcl-2 but not Bax or p53 correlates with in vitro resistance to a series of anticancer drugs in breast carcinoma. 1096 97

It has been established that melatonin (Mlt) and retinoic acid, individually, inhibit the proliferation of the estrogen receptor-alpha (ER alpha)-positive MCF-7 breast cancer cell line. Our laboratory has previously demonstrated that Mlt and all-trans-retinoic acid (atRA) not only inhibit the proliferation, but also induce apoptosis of MCF-7 cells when used in a sequential regimen of Mlt followed 24 h later by atRA. Using this same MCF-7 breast cancer cell line, we investigated the potential pathways through which apoptosis is being induced. We found that treatment of MCF-7 cells with Mlt for 24 h before the addition of atRA decreased the protein levels of the death suppressor, Bcl-2, and increased, although with different time courses, the levels of the death promoters, Bax and Bak; however, there was no change in the levels of the tumor suppressor gene, p53. MCF-7 cells treated sequentially with Mlt and atRA also demonstrated an enhanced sensitivity to the apoptotic effects of atRA, which did not appear to be due to increased expression of the retinoic acid receptors, RAR alpha or RXR alpha, but rather to enhanced transcriptional activity of the RAR alpha. These data suggest that the sequential treatment regimen of Mlt and atRA may induce apoptosis by modulation of members of the Bcl-2 family of proteins. Thus, this combinatorial regimen, which reduces the concentration of atRA needed for clinical efficacy while enhancing its anti-tumorigenic activity, could be of great therapeutic benefit, and may, in fact, specifically induce the regression of established breast tumors due to its apoptosis-promoting effects.
Breast Cancer Res Treat 2000 Jun
PMID:Pathways through which a regimen of melatonin and retinoic acid induces apoptosis in MCF-7 human breast cancer cells. 1096 99

Chemotherapy or irradiation treatment induces breast cancer cell apoptosis, but this can be limited by estradiol (E2) through unknown mechanisms. To investigate this, we subjected estrogen receptor-expressing human breast cancer cells (MCF-7 and ZR-75-1) to paclitaxel (taxol) or to UV irradiation. Marked increases in cell apoptosis were induced, but these were significantly reversed by incubation with E2. Taxol or UV stimulated c-Jun N-terminal kinase (JNK) activity, which was inhibited by E2. Expression of a dominant-negative Jnk-1 protein strongly prevented taxol- or UV-induced apoptosis, whereas E2 inhibition of apoptosis was reversed by expression of constituitively active Jnk-1. As targets for participation in apoptosis, Bcl-2 and Bcl-xl were phosphorylated in response to JNK activation by taxol or UV; this was prevented by E2. Taxol or UV activated caspase activity in a JNK-dependent fashion and caused the cleavage of procaspase-9 to caspase-9, each inhibited by E2. Independently, the steroid also activated extracellular signal-regulated protein kinase activity, which contributed to the antiapoptotic effects. We report novel and rapid mechanisms by which E2 prevents chemotherapy or radiation-induced apoptosis of breast cancer, probably mediated through the plasma membrane estrogen receptor.
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PMID:Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer. 1097 21

Flavopiridol is an inhibitor of several cyclin-dependent kinases, and exhibits potent growth-inhibitory activity against a number of human tumor cell lines both in vitro, and when grown as xenografts in mice. It has shown promising antineoplastic activity and is currently undergoing clinical phase II testing. Prostate cancer (PCa) remains a leading cause of morbidity and mortality among males in the United States. There are no effective treatments for hormone and/or radiation refractory PCa, suggesting that novel and newer treatment strategy may be useful in the management of PCa. Our previous study showed that flavopiridol induces cell growth inhibition and apoptosis in breast cancer cells. Here, we investigated whether flavopiridol was effective against prostate cancer cells. Flavopiridol was found to inhibit growth of PC3 prostate cancer cells. Induction of apoptosis was also observed in PC3 cells treated with flavopiridol, as measured by DNA laddering and PARP cleavage. We also found a significant down-regulation of Bcl-2 in flavopiridol-treated cells. These findings suggest that down-regulation of Bcl-2 may be one of the molecular mechanisms through which flavopiridol induces apoptosis and inhibits cell growth, suggesting that flavopiridol may be an effective chemotherapeutic agent against prostate cancer.
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PMID:Induction of growth inhibition and apoptosis in prostate cancer cells by flavopiridol. 1099 88

We report that transfection of insulin-like growth factor-binding protein-3 (IGFBP-3) cDNA in human breast cancer cell lines expressing either mutant p53 (T47D) or wild-type p53 (MCF-7) induces apoptosis. IGFBP-3 also increases the ratio of pro-apoptotic to anti-apoptotic members of the Bcl-2 family. In MCF-7, an increase in Bad and Bax protein expression and a decrease in Bcl-x(L) protein and Bcl-2 protein and mRNA were observed. In T47D, Bax and Bad proteins were up-regulated; Bcl-2 protein is undetectable in these cells. As T47D expresses mutant p53 protein, these modulations of pro-apoptotic proteins and induction of apoptosis are independent of p53. The effect of IGFBP-3 on the response of T47D to ionizing radiation (IR) was examined. These cells do not G(1) arrest in response to IR and are relatively radioresistant. Transfection of IGFBP-3 increased the radiosensitivity of T47D and increased IR-induced apoptosis but did not effect a rapid G(1) arrest. IR also caused a much greater increase in Bax protein in IGFBP-3 transfectants compared with vector controls. Thus, IGFBP-3 increases the expression of pro-apoptotic proteins and apoptosis both basally and in response to IR, suggesting it may be a p53-independent effector of apoptosis in breast cancer cells via its modulation of the Bax:Bcl-2 protein ratio.
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PMID:Insulin-like growth factor-binding protein-3 modulates expression of Bax and Bcl-2 and potentiates p53-independent radiation-induced apoptosis in human breast cancer cells. 1099 26

Recent experiments suggest an interconnection between cell proliferation and programmed cell death (apoptosis), although the detailed molecular mechanisms remain unclear. We have hypothesized that expression of some apoptosis regulators is cell cycle-dependent, which in turn influences tumor cell chemosensitivity in a cell cycle-dependent fashion. To test these hypotheses, we synchronized human leukemia Jurkat T, Neo (using aphidicolin), breast cancer MCF-7, normal fibroblast, and simian virus 40-transformed cells (by aphidicolin or serum starvation), and measured levels of several Bcl-2 family proteins. The highest expression of Bcl-2 protein was found in the G(1) phase of all the five cell lines tested. In contrast, levels of Bax protein remained relatively unchanged in four of the cell lines, and levels of Bcl-X(L), Bcl-X(S), and Bak proteins showed little or no cell cycle-dependent changes in Jurkat T cells. Similar to the changes in Bcl-2 protein levels, its mRNA expression was also G(1) phase-specific, whereas the level of a Bcl-2 cleavage activity remained constitutive. When treated with an anticancer drug (etoposide or cisplatin) or the kinase inhibitor staurosporin, the cells containing a high G(1) population and a high Bcl-2 protein level were much more resistant to the induced apoptosis than the cells containing a high S phase population and a low Bcl-2 protein level. Constitutive overexpression of Bcl-2 protein in Jurkat T cells completely blocked the S phase-associated sensitivity to these apoptosis stimuli. The cell cycle-dependent Bcl-2 protein expression seems to contribute to the regulation of chemosensitivity and apoptotic commitment of human tumor cells.
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PMID:G(1) phase-dependent expression of bcl-2 mRNA and protein correlates with chemoresistance of human cancer cells. 1104 47


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