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

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/APO-2L) induces apoptosis in a variety of tumour cells upon binding to death receptors TRAIL-R1 and TRAIL-R2. Here we describe the sensitization by interferon (IFN)-gamma to TRAIL-induced apoptosis in the breast tumour cell lines MCF-7 and MDA-MB231. IFN-gamma promoted TRAIL-mediated activation of caspase-8, Bcl-2 interacting domain death agonist (Bid) degradation, Bcl-2-associated X protein (Bax) translocation to mitochondria, cytochrome c release to the cytosol and activation of caspase-9 in these cell lines. No changes in the expression of TRAIL receptors were observed upon IFN-gamma treatment. Overexpression of Bcl-2 in MCF-7 cells completely inhibited IFN-gamma-induced sensitization to TRAIL-mediated cell death. Interestingly, TRAIL-induced apoptosis was also clearly enhanced by IFN-gamma in caspase-3-overexpressing MCF-7 cells, in the absence of Bax translocation to mitochondria and cytochrome c release to the cytosol. In summary, our results suggest that IFN-gamma facilitates TRAIL-induced activation of mitochondria-regulated as well as mitochondria-independent apoptotic pathways in breast tumour cells.
 ...
PMID:Mitochondria-dependent and -independent mechanisms in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis are both regulated by interferon-gamma in human breast tumour cells. 1193 54

Previous experimental studies have shown that high dietary fat intake is associated with mammary carcinogenesis. In the current study, the effect of 5-LOX or 12-LOX inhibitors on human breast cancer cell proliferation and apoptosis, as well as the possible mechanisms were investigated. The LOX inhibitors, NDGA, Rev-5901, and baicalein all inhibited proliferation and induced apoptosis in MCF-7 (ER+) and MDA-MB-231 (ER-) breast cancer cell in vitro. In contrast, the LOX products, 5-HETE and 12-HETE had mitogenic effects, stimulating the proliferation of both cell lines. These inhibitors also induced cytochrome c release, caspase-9 activation, as well as downstream caspase-3, caspase-7 activation, and PARP cleavage. LOX inhibitor treatment also reduced the levels of anti-apoptotic proteins Bcl-2 and Mcl-1 and increased the levels of the pro-apoptotic protein bax. In conclusion, blockade of both 5-LOX and 12-LOX pathways induces apoptosis in breast cancer cells through the cytochrome c release and caspase-9 activation, with changes in the levels of Bcl-2 family proteins.
 ...
PMID:The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer cells. 1220 Jan 39

Reduction in apoptosis has been associated with tumor metastases and response to chemotherapy in breast cancer. We examine the influence of apoptosis status and the expression of antiapoptotic proteins Bcl-2 and Bcl-x(L) on metastatic progression and response to therapy in an experimental model of breast cancer. We used human breast cancer cells (MDA-MB 435, MDA-MB 468 and MCF-7) to induce orthotopic xenograft tumors in nude mice. The overexpression of Bcl-2 or Bcl-x(L) influenced tumorigenicity, 468 transfectants being less tumorigenic than control (p < 0.0001). Lung metastasis appeared at day 120 in animals injected with 435/Bcl-2 or 435/Bcl-x(L) and they showed higher metastatic activity than control 435/Neo tumors (p = 0.02). In contrast, mice with 468 tumors were followed for 1 year after tumor excision, but they did not develop metastatic foci. 435/Bcl-2 and 435/Bcl-x(L) transfectant cells bound less readily to laminin (ANOVA, p < 0.0001), fibronectin (ANOVA, p < 0.0001) and collagen type-IV (ANOVA, p < 0.0001) than 435/Neo cells. The overexpression of antiapoptotic proteins in 435 transfectants rescued 20-40% of cells from anoikis at 64 hr in rocking conditions. In contrast, at this time only 5-10% of 468 and MCF-7 transfectant cells were rescued. Thus, the overexpression of the Bcl-2 or Bcl-x(L) associated with the loss of apoptosis in breast cancer cells in vivo may account for their metastatic behavior. These genes increase tumor metastasis when the oncogenic background has triggered the metastatic process, in which anoikis might determine tumor progression when the life span of the cells is extended.
 ...
PMID:Inhibition of apoptosis in human breast cancer cells: role in tumor progression to the metastatic state. 1220 55

Disruption of apoptosis may allow metastatic cell survival and confer resistance to chemotherapeutic drugs. We have analysed the molecular pathways that activate these survival genes in specific sites of metastasis. Estrogen receptor-negative breast cancer cell line MDA-MB435 and two metastatic sublines derived from lung (435L) and brain (435B) were analysed for the expression of members of the Bcl-2 family of apoptosis regulators. The levels of Bcl-2 were higher in the metastatic sublines than in parental cells, which correlated with the activation of Stat3, but not with the expression and/or activation of known bcl-2 transcription factors (CREB and WT1). In the brain subline, both expression of Bcl-2 and Stat3 activation were induced by epidermal growth factor and abrogated after treatment with kinase inhibitors specific for epidermal growth factor receptor or Jak2. Furthermore, transfection of 435B with a dominant-negative Stat3 markedly reduced the expression of Bcl-2 protein, whereas transient expression of a constitutively active Stat3 increased Bcl-2 in parental 435 cells. In addition, blockade of Stat3 activation by treatment with epidermal growth factor receptor and Jak2 kinase inhibitors or transfection with a dominant negative Stat3, sensitizes 435B cells to chemotherapy-induced apoptosis. Our data suggest that an increased activation of the Stat3-Bcl-2 pathway in estrogen receptor-negative metastatic breast cancer cell lines confer a survival advantage to these cells and contribute to their chemoresistance.
 ...
PMID:Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. 1240 4

(-)-Epigallocatechin (EGC), one of green tea polyphenols, has been shown to inhibit growth of cancer cells. However its mechanism of action is poorly known. We show here that EGC strongly inhibited the growth of breast cancer cell lines (MCF-7 and MDA-MB-231) but not that of normal breast epithelial cells. The inhibition of breast cancer cell growth was due to an induction of apoptosis, without any change in cell cycle progression. MCF-7 cells are known to express a wild-type p53 whereas MDA-MB-231 cells express a mutated p53. The fact that EGC induced apoptosis in both these cell lines suggests that the EGC-triggered apoptosis is independent of p53 status. Moreover, neutralizing antibodies against the death receptor Fas and inhibitors of caspases, such as caspase-8 and -10, efficiently inhibited the EGC-triggered apoptosis. In addition, immunoblotting revealed that EGC treatment was correlated with a decrease in Bcl-2 and an increase in Bax level. These results suggest that EGC-triggered apoptosis in breast cancer cells requires Fas signaling.
 ...
PMID:(-)-Epigallocatechin (EGC) of green tea induces apoptosis of human breast cancer cells but not of their normal counterparts. 1246 80

Bcl-2 family members have been shown to be key mediators of apoptosis as either pro- or anti-apoptotic factors. It is thought that both classes of Bcl-2 family members act at the level of the mitochondria to regulate apoptosis, although the founding anti-apoptotic family member, Bcl-2 is localized to the endoplasmic reticulum (ER), mitochondrial, and nuclear membranes. In order to better understand the effect of Bcl-2 localization on its activity, we have utilized a Bcl-2 mutant that localizes only to the ER membrane, designated Bcl-2Cb5. Bcl-2Cb5 was expressed in MDA-MB-468 cells, which protected against apoptosis induced by the kinase inhibitor, staurosporine. Data presented here show that Bcl-2Cb5 inhibits this process by blocking Bax activation and cytochrome c release. Furthermore, we show that Bcl-2Cb5 can inhibit the activation of a constitutively mitochondrial mutant of Bax, indicating that an intermediate between Bcl-2 on the ER and Bax on the mitochondria must exist. We demonstrate that this intermediate is likely a BH3-only subfamily member. Data presented here show that Bcl-2Cb5 can sequester a constitutively active form of Bad (Bad3A) from the mitochondria and prevent it from activating Bax. These data suggest that Bcl-2 indirectly protects mitochondrial membranes from Bax, via BH3-only proteins.
 ...
PMID:Bcl-2 on the endoplasmic reticulum regulates Bax activity by binding to BH3-only proteins. 1247 29

The human retinoic acid receptor beta (RARbeta) has three isoforms (beta1, beta2, and beta4), which play important, distinct roles in mediating the effects of retinoic acid on cell growth and apoptosis. Whereas RARbeta2 is a potent inhibitor of breast cancer cell proliferation, RARbeta4 can act as a dominant-negative repressor of RARbeta2-mediated growth suppression. In this study we investigated the effects of all-trans-retinoic acid (ATRA) on two clones derived from the breast cancer cell line MDA-MB-435: a non-metastatic clone (NM-2C5) and a metastatic clone (M-4A4). ATRA treatment of the NM-2C5 cells resulted in growth inhibition and apoptosis, whereas the M-4A4 cells were resistant to ATRA. Analyses of the expression of RARbeta isoforms revealed that the sensitive NM-2C5 clone expressed only RARbeta2, whereas the resistant M-4A4 cells expressed both RARbeta2 and RARbeta4 mRNA and protein. ATRA treatment increased RARbeta2 mRNA level in NM-2C5 cells, whereas the same treatment of the M-4A4 cells resulted in an increase in RARbeta4 and a decrease in RARbeta2 mRNA. ATRA treatment of NM-2C5 cells increased the protein levels of the histone acetyl transferases p300 and CBP, suppressed the level of histone deacetylase and increased the level of acetylated histone H4. ATRA also decreased Bcl-2 and increased Bax and decreased VEGF. In contrast, the same treatment of the M-4A4 cells resulted in opposite effects. These results suggest that the effects of ATRA on the growth of the metastatic and non-metastatic breast cancer cell lines depend on the expression of RARbeta isoforms and that the expression of RARbeta4 may contribute to metastatic properties.
 ...
PMID:Differential effects of retinoic acid on the growth of isogenic metastatic and non-metastatic breast cancer cell lines and their association with distinct expression of retinoic acid receptor beta isoforms 2 and 4. 1257 17

Overexpression of the HER-2 correlates with drug-resistance and a poor prognosis in breast cancer, however the mechanism(s) of HER-2-mediated drug-resistance are unknown. We examined the effects of antisense Bcl-2 and HER-2 oligonucleotides (ODN) to assess the mechanism(s) through which down-regulation of Bcl-2 and HER-2 enhances drug-sensitivity. Using two human breast cancer cell lines, MDA-MB-231 and BT-474, the antitumor effects of a combination of antisense ODN and anticancer drugs, including mitomycin C (MMC), adriamycin (ADM), paclitaxel (TXL), and docetaxel (TXT) was evaluated. The expression of Bcl-2 protein was suppressed by treatment with antisense Bcl-2 ODN in a dose-dependent manner. An enhanced drug-sensitivity to MMC and TXL upon pretreatment with antisense Bcl-2 ODN was observed, with the IC50 values increasing 1.9- and 2.0-fold, respectively. Treatment of BT-474 cells with antisense HER-2 at 1.0 micro M suppressed HER-2 overexpression by 60.5%. Pretreatment with antisense HER-2 ODN increased the sensitivity of these cells to ADM and TXL 20.8- and 10.8-fold, respectively. In vivo experiments using a combination of antisense HER-2 and TXL showed the similar enhancement of antitumor effect of TXL as compared to that of antisense HER-2 or TXL alone (p=0.068). Enhancement of drug-sensitivity was associated with the induction of apoptosis. Of interest, treatment with antisense HER-2 ODN also suppressed the expression of Bcl-2 and pAkt. These results indicate that down-regulation of Bcl-2 and HER-2 increased drug-sensitivity by modulating drug-induced apoptotic pathways in breast cancer cells, and that antisense ODN therapy, targeting Bcl-2 and HER-2 may be a useful strategy to enhance drug-sensitivity.
 ...
PMID:Antisense Bcl-2 and HER-2 oligonucleotide treatment of breast cancer cells enhances their sensitivity to anticancer drugs. 1263 82

TNF-related apoptosis-inducing ligand (TRAIL) is known to selectively induce apoptosis in various tumour cells. However, downstream-signalling of TRAIL-receptor is not well defined. A functional genetic screening was performed to isolate genes interfering with TRAIL-induced apoptosis using cDNA retroviral library. Bcl-X(L) and FLIP were identified after DNA sequencing analysis of cDNA rescued from TRAIL-resistant clones. We found that increased expression of Bcl-X(L), but not Bcl-2, suppressed TRAIL-induced apoptosis in tumour cells. Western blot and immunohistochemical analyses showed that expression of Bcl-X(L), but not Bcl-2, was highly increased in human breast cancer tissues. Exposure of MDA-MB-231 breast tumour cells to TRAIL induced apoptosis accompanied by dissipation of mitochondrial membrane potential and enzymatic activation of caspase-3, -8, and -9. However, SK-BR-3 breast tumour cells exhibiting increased expression level of Bcl-X(L) were resistant to TRAIL, though upon exposure to TRAIL, caspase-8 and Bid were activated. Forced expression of Bcl-X(L), but not Bcl-2, desensitised TRAIL-sensitive MDA-MB-231 cells to TRAIL. Similar inhibitory effects were also observed in other tumour cells such as HeLa and Jurkat cells stably expressing Bcl-X(L), but not Bcl-2. These results are indicative of the crucial and distinct function of Bcl-X(L) and Bcl-2 in the modulation of TRAIL-induced apoptosis.
 ...
PMID:Functional screening of genes suppressing TRAIL-induced apoptosis: distinct inhibitory activities of Bcl-XL and Bcl-2. 1264 29

2-Methoxyestradiol (2-ME2) is a natural estrogen metabolite that, while devoid of estrogenic effects, has both antiangiogenic and antitumor effects. 2-ME2 is currently being evaluated in Phase I and Phase II clinical trials for the treatment of multiple types of cancer. Novel analogues of 2-ME2 were tested for activities that predict antiangiogenic and antitumor effects. Selected analogues were tested for inhibitory activity against endothelial cell proliferation and invasion. The results show that these analogues are effective inhibitors of endothelial cell activities that may predict antiangiogenic activity, and one analogue, 2-methoxy-14-dehydroestradiol (14-dehydro-2-ME2), was 6-15-fold more potent than the parental compound in these assays. The analogues were also evaluated for inhibition of proliferation and cytotoxicity against multiple tumor cell lines and found to be potent and effective. 14-Dehydro-2-ME2 was approximately 15-fold more potent than 2-ME2 against various tumor cell lines, and 2-methoxy-15-dehydroestradiol was particularly effective against DU 145 and PC3 prostate cancer cell lines. In vivo antitumor activity was observed for the three analogues tested in the murine xenograft MDA-MB-435 model; however, 2-ME2 provided no antitumor activity in this trial. The two most effective analogues, 14-dehydro-2-ME2 and 2-methoxyestradiol-15 alpha,16 alpha-acetonide, provided 29.4% and 26.7% inhibition of tumor burden, respectively. Mechanism of action studies indicate that the analogues cause mitotic spindle disruption, mitotic arrest, microtubule depolymerization, and inhibition of the assembly of purified tubulin similar to the effects of 2-ME2. Consistent with antimitotics that inhibit the dynamic instability of tubulin and initiate apoptosis, these novel 2-ME2 analogues cause Bcl-2 phosphorylation and activation of mitogen-activated protein kinase signaling pathways.
 ...
PMID:Novel 2-methoxyestradiol analogues with antitumor activity. 1267 Sep 2


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>