Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular mechanisms underlying the cell cycle growth-inhibitory and apoptotic effects of flavopiridol (FP) were determined in human breast cancer cells. Treatment with FP caused accumulation in the G(1) phase of the cell cycle and induced apoptosis of SKBR-3 and MB-468 cells. This was associated with down-regulation of the levels of cyclins D1 and B1, as well as with inhibition of cyclin-dependent kinase (cdk) 1, cdk2, and cdk4. FP-induced apoptosis was accompanied by a conformational change and mitochondrial localization of Bax. This resulted in the accumulations of cytochrome c, Smac, and Omi/HtrA2 in the cytosol and induced the poly(ADP-ribose) polymerase cleavage activity of caspase-3. Treatment with FP also attenuated the mRNA and protein levels of XIAP, cIAP-2, Mcl-1, Bcl-x(L), and survivin. In MB-468 cells with overexpression of Bcl-2 (468/Bcl-2), FP-induced Bax conformational change and apoptosis were inhibited, whereas the FP-mediated decline in the levels of IAP proteins, Mcl-11 and Bcl-x(L) remained unaltered. The effects of cotreatment with FP and the nontaxane tubulin-polymerizing agent epothilone (Epo) B were also determined in MB-468 cells. Sequential treatment with Epo B followed by FP induced significantly more apoptosis of MB-468 cells than treatment with the reverse sequence of FP followed by Epo B or treatment with either agent alone (P < 0.05). Treatment with Epo B followed by FP induced more Bax conformational change and was associated with a greater decline in the levels of XIAP, cIAP-2, Mcl-1, and Bcl-x(L). However, MB-468/Bcl-2 cells remained relatively resistant to Epo B followed by FP. Taken together, these findings suggest that the superior sequence-dependent anti-breast cancer activity of Epo B followed by FP may be due to FP-induced Bax conformational change and down-regulation of the antiapoptotic IAP, Bcl-x(L), and Mcl-1 proteins, but this treatment may not overcome the resistance to apoptosis of breast cancer cells conferred by overexpression of Bcl-2.
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PMID:Flavopiridol down-regulates antiapoptotic proteins and sensitizes human breast cancer cells to epothilone B-induced apoptosis. 1251 83

The objective of the present study was to evaluate the effect of beta-sitosterol, a plant sterol that induces apoptosis in breast cancer cells, on two pathways leading to apoptosis. These pathways are classified based on the localization of the initiated signal, extrinsic and intrinsic pathways. Extrinsic and intrinsic pathways are catalyzed by caspases 8 and 9, respectively, which leads to the activation of the executioner caspase 3. The results of the present study indicate that beta-sitosterol supplementation at 16 microM for 3 days to MDA-MB-231 cells induces 39% and 80% increases in the activities of caspases 8 and 9, respectively, compared to cholesterol supplemented cells or controls. There was also a 3-fold increase in the activity of caspase 3. Sterol treatment had no effect on the quantities of the enzymes. It is concluded that beta-sitosterol may induce apoptosis through the two pathways but was more pronounced on the intrinsic pathway.
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PMID:Beta-sitosterol, a plant sterol, induces apoptosis and activates key caspases in MDA-MB-231 human breast cancer cells. 1257 96

Farnesyl transferase inhibitors (FTIs) serve to specifically inhibit farnesyl isoprenoid lipid modification of proteins. Although originally developed as anti-Ras oncoprotein drugs, it now appears that these compounds function independently of Ras. FTIs have been shown to inhibit transformation by a variety of mechanisms, including apoptosis involving cytochrome c release from mitochondria. Tamoxifen exhibits both anti-estrogenic and estrogenic properties and is widely used as an estrogen antagonist for the treatment of estrogen receptor (ER) positive human breast tumors. Tamoxifen can induce ER-dependent apoptosis in human breast tumor cells by a mechanism involving the Bcl2/mitochondrial arm of the apoptotic machinery. Since tamoxifen and FTIs may stimulate distinct components of the mitochondrial-based apoptotic machinery, we reasoned that their effects might be synergistic. Here we show that anti-estrogens and an FTI (FTI-277) synergize to inhibit cell growth and enhance cell death in ER positive, human breast tumor cell lines. However, the drugs exhibited only additive effects on an ER negative cell line. Analysis of treated ER positive T-47D cells demonstrated that a synergistic increase in apoptosis was induced, as measured by increased caspase 3 activity. Thus, tamoxifen and FTIs may synergize to promote apoptotic cell death in ER positive human breast tumor cells.
Breast Cancer Res Treat 2003 Mar
PMID:Tamoxifen and the farnesyl transferase inhibitor FTI-277 synergize to inhibit growth in estrogen receptor-positive breast tumor cell lines. 1261 58

Signal transducer and activator of transcription (Stat) 5 regulates growth, differentiation, and survival of mammary and hematopoietic cells. The role of Stat5 in breast cancer has not been established, although Stat5 is critical for some hematopoietic malignancies. We detected for the first time that Stat5b is constitutively activated in human breast cancer cell lines, and analysed the role of Stat5 in estrogen receptor(ER)-positive breast cancer cell lines using dominant-negative variants of Stat5. Two distinct carboxyl-truncated Stat5a derivatives were generated. Stat5aDelta740 corresponded to a naturally occurring alternative splice variant, and Stat5aDelta713 was analogous to an 80 kDa Stat5a product of a nuclear protease. Stat5aDelta740 and Stat5aDelta713 displayed comparable dominant-negative properties and suppressed transcriptional activity of wild-type Stat5a and Stat5b equally well. Cotransfection experiments revealed that Stat5aDelta740 completely blocked transcriptional activity of endogenous estrogen receptor in T47D and MCF7 cells, and of both ER alpha and ER beta in COS-7 cells. Stat5aDelta740 was selected for adenoviral delivery, and high-efficiency expression of tyrosine phosphorylated Stat5aDelta740 was achieved in infected cells. Adenoviral-mediated Stat5aDelta740 induced apoptosis in T47D cells but not in caspase-3-negative MCF7 cells. The present study indicates that overexpression of a dominant-negative variant of Stat5 suppresses ER transcriptional activity and induces apoptosis in estrogen-responsive breast cancer tissue culture cells.
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PMID:Naturally occurring dominant-negative Stat5 suppresses transcriptional activity of estrogen receptors and induces apoptosis in T47D breast cancer cells. 1264 67

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.
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PMID:Functional screening of genes suppressing TRAIL-induced apoptosis: distinct inhibitory activities of Bcl-XL and Bcl-2. 1264 29

Focal adhesion kinase (FAK) has a central role in adhesion-mediated cell signalling. The N-terminus of FAK is thought to function as a docking site for a number of proteins, including the Src-family tyrosine kinases. In the present study, we disrupted FAK signalling by expressing the N-terminal domain of FAK (FAK-NT) in human breast carcinoma cells, BT474 and MCF-7 lines, and non-malignant epithelial cells, MCF-10A line. Expression of FAK-NT led to rounding, detachment and apoptosis in human breast cancer cells. Apoptosis was accompanied by dephosphorylation of FAK Tyr(397), degradation of the endogenous FAK protein and activation of caspase-3. Over-expression of FAK rescued FAK-NT-mediated cellular rounding. Expression of FAK-NT in non-malignant breast epithelial cells did not lead to rounding, loss of FAK phosphorylation or apoptosis. Thus FAK-NT contributes to cellular adhesion and survival pathways in breast cancer cells which are not required for survival in non-malignant breast epithelial cells.
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PMID:Focal adhesion kinase N-terminus in breast carcinoma cells induces rounding, detachment and apoptosis. 1265 33

Aplidine is a promising antitumor agent derived from the Mediterranean tunicate Aplidium albicans. We have found that Aplidine at nM concentrations (10-100 nM) induced apoptosis in human leukemic cell lines and primary leukemic cell cultures from leukemic patients. Inhibition of the Fas (CD95)/Fas ligand (CD95L) signaling pathway with an antagonistic anti-Fas antibody partially inhibited Aplidine-induced apoptosis. L929 cells were resistant to Aplidine action but underwent apoptosis after transfection with human Fas cDNA. Aplidine induced a rapid and sustained c-Jun NH(2)-terminal kinase activation, and pretreatment with curcumin or SP600125 inhibited Aplidine-induced c-Jun NH(2)-terminal kinase activation and apoptosis. However, inhibition of extracellular signal-regulated kinase and p38 kinase signaling pathways did not affect Aplidine-induced apoptosis. Aplidine induced caspase-3 activation, and caspase inhibition prevented Aplidine-induced apoptosis. Aplidine failed to induce apoptosis in MCF-7 breast cancer cells, defective in caspase-3, additionally implicating caspase-3 in its proapoptotic action. Aplidine also triggered an early release of cytochrome c from mitochondria, and overexpression of bcl-2 by gene transfer abrogated mitochondrial cytochrome c release and apoptosis. Aplidine rapidly induced cleavage of Bid, a mediator that connects the Fas/CD95 cell death receptor to the mitochondrial apoptosis pathway. Primary cultures of normal human cells, including hepatocytes and resting peripheral blood lymphocytes, were spared or weakly affected after Aplidine treatment. Nevertheless, mitogen (phytohemagglutinin/interleukin-2)-activated T lymphocytes resulted sensitively to the apoptotic action of Aplidine. Thus, Aplidine is an extremely potent and rapid apoptotic inducer on leukemic cells that triggers Fas/CD95- and mitochondrial-mediated apoptotic signaling routes, and shows a rather selective apoptotic action on cancer cells and activated T cells.
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PMID:Rapid and selective apoptosis in human leukemic cells induced by Aplidine through a Fas/CD95- and mitochondrial-mediated mechanism. 1268 30

Onset of the mitochondrial permeability transition (MPT) causes both necrotic and apoptotic cell death in cultured hepatocytes. Salicylate lowers the threshold for onset of the MPT. In this study, our aim was to determine whether nontoxic concentrations of salicylate potentiate MPT-mediated cell killing. In necrotic killing models to rat hepatocytes, salicylate (1 mM) enhanced calcium ionophore (Br-A23187)- and tert-butylhydroperoxide (t-BuOOH)-induced cell death, which was blocked or delayed by cyclosporin A (CsA, 2 microM), a specific inhibitor of the MPT. In hepatocyte apoptosis induced by tumor necrosis factor-alpha (TNF-alpha), salicylate accelerated cell killing after low-dose TNF-alpha (1 ng/ml), which by itself induced little apoptosis. Salicylate enhancement of apoptosis was associated with onset of the MPT and accelerated caspase 3 activation. Salicylate also augmented killing of MCF-7 human breast tumor cells by etoposide and PLC/PRF/5 human hepatoma cells by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In conclusion, salicylate potentiates both necrotic and apoptotic cell killing by promoting onset of the MPT. Enhancement by salicylate of MPT-dependent apoptosis may play a role in protection by aspirin and other nonsteroidal anti-inflammatory drugs against colon, lung, and breast cancer.
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PMID:Salicylate enhances necrosis and apoptosis mediated by the mitochondrial permeability transition. 1270 Apr 12

Estrogens promote cell proliferation in normal and transformed mammary epithelial cells by inducing expression of hormone-responsive genes involved in the cell cycle. The action of antiestrogens is therefore central in regard to their potent inhibitory effects on estrogen-induced cell growth. We used normal human epithelial breast cells from primary cultures (HBE cells) to study hormonal (estrogen and antiestrogen) regulation on 3 key proteins involved in the apoptotic process: Bcl-2, p53 and caspase-3. The mammary adenocarcinoma cell line, MCF-7, was also used to study the molecular regulation of Bcl-2. In both HBE and MCF-7 cells, we found that estradiol (E2) induced an increase in Bcl-2 mRNA levels. This effect was counteracted in the presence of a pure antiestrogen, ICI 182780 (ICI). Alone, ICI did not modify either the Bcl-2 protein or mRNA levels in HBE cells, whereas in MCF-7, a strong downregulation of Bcl-2 mRNA was observed. In parallel, in HBE cells, we observed that E2 caused a decrease in p53 and caspase-3 protein levels, whereas ICI alone increased p53 and caspase-3 protein levels. The ICI effects on p53 and caspase-3 were partially counteracted by E2. Under the same experimental conditions, ICI exerts a potent pro-apoptotic effect, which was not counteracted by E2. In contrast, 4-hydroxytamoxifen was slightly weaker as a pro-apoptotic agent in HBE cells and its effects were reversed by E2. We demonstrate that in HBE cells, ICI reverses the anti-apoptotic action of E2 and alone acts as a highly potent pro-apoptotic molecule. These results provide new insight into treatment for breast cancer prevention.
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PMID:Antiestrogens are pro-apoptotic in normal human breast epithelial cells. 1274 Sep 7

Pentagalloylglucose (5GG) is a potent and specific inhibitor of NADPH dehydrogenase or xanthine oxidase. In our previous study, we showed that 5GG was able to induce apoptosis in HL-60 cells in a time- and concentration-dependent manner via the activation of caspase-3. Recently, we found that 5GG was capable of perturbing the cell cycle of the human breast cancer cell line MCF-7. DNA flow cytometric analysis showed that 5GG exhibited the ability of blocking MCF-7 cell cycle progression at the G1 phase. The level of several G1 phase-related cyclins and cyclin-dependent kinases did not change in these cells during a 24-hr exposure to 5GG. However, the activity of cyclin E/CDK2 was decreased in a concentration- and time-dependent manner and the activity of cyclin D/CDK4 was inhibited when serum-starved synchronized cells were released from synchronization. p27(Kip) and p21(Cip), inhibitors of cyclin/CDK complexes in G1-phase, were gradually increased after 5GG treatment in a time-dependent manner and the induction of p21(Cip) was correlated with an increase in p53 levels. These results suggest that the suppression of cell-cycle progression in the G1 phase by 5GG was mediated in MCF-7 cells, at least in part, by either the inhibition of cyclin D/CDK4 and cyclin E/CDK2 activity or the induction of the CDK inhibitors p27(Kip) and p21(Cip).
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PMID:Induction of G1 phase arrest in MCF human breast cancer cells by pentagalloylglucose through the down-regulation of CDK4 and CDK2 activities and up-regulation of the CDK inhibitors p27(Kip) and p21(Cip). 1278 29


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