Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) are protein-tyrosine kinases that are overexpressed and activated in human breast cancer. To determine the role of EGFR and FAK survival signaling in breast cancer, EGFR was stably overexpressed in BT474 breast cancer cells, and each signaling pathway was specifically targeted for inhibition. FAK and EGFR constitutively co-immunoprecipitated in EGFR-overexpressing BT474 cells. In low EGFR-expressing BT474-pcDNA3 vector control cells, inhibition of FAK by the FAK C-terminal domain caused detachment and apoptosis via pathways involving activation of caspase-3 and -8, cleavage of poly(ADP-ribose) polymerase, and caspase-3-dependent degradation of AKT. This apoptosis could be rescued by the dominant-negative Fas-associated death domain, indicating involvement of the death receptor pathway. EGFR overexpression did not inhibit detachment induced by the FAK C-terminal domain, but did suppress apoptosis, activating AKT and ERK1/2 survival pathways and inhibiting cleavage of FAK, caspase-3 and -8, and poly(ADP-ribose) polymerase. Furthermore, this protective effect of EGFR signaling was reversed by EGFR kinase inhibition with AG1478. In addition, inhibition of FAK and EGFR in another breast cancer cell line (BT20) endogenously overexpressing these kinases also induced apoptosis via the same mechanism as in the EGFR-overexpressing BT474 cells. The results of this study indicate that dual inhibition of FAK and EGFR signaling pathways can cooperatively enhance apoptosis in breast cancers.
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PMID:Dual inhibition of focal adhesion kinase and epidermal growth factor receptor pathways cooperatively induces death receptor-mediated apoptosis in human breast cancer cells. 1216 18

Caspase-3 activity has been described to be essential for drug-induced apoptosis. Recent results suggest that in addition to its downstream executor function, caspase-3 is also involved in the processing of upstream caspase-8 and -9. To test the absolute requirement for caspase-3, we examined mitomycin C (MMC)-induced apoptosis in the caspase-3 deficient human breast cancer cell line MCF-7. MMC was used as anticancer drug since this agent was preferentially active compared to chemotherapeutic compounds with differing mechanisms of action such as cisplatin, docetaxel, or lovastatin. MMC treatment led to pronounced caspase-8, -9, and -7 processing and early morphological features of apoptosis within 48 h. This could be inhibited by the broad-spectrum caspase inhibitor z-VAD.fmk and to a lesser extent by z-IETD.fmk and z-LEHD.fmk, which have a certain preference for inhibiting caspase-8 and -9, respectively. MMC induced apoptosis in MCF-7 cells was not mediated by the death receptor pathway as demonstrated by experiments using the inhibiting anti-Fas antibody ZB4 and transfections with CrmA, a viral serpin inhibitor of caspase-8, and the dominant negative Fas-associated death domain (FADD-DN). Stable expression with Bcl-2 significantly prevented the processing of caspase-9 but also of caspase-8 and blocked the induction of apoptosis. Thus, we provide evidence that caspase-3 activity is dispensable for MMC-induced apoptosis and for caspase-8 and -9 processing in MCF-7 cells.
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PMID:Mitomycin C induces apoptosis and caspase-8 and -9 processing through a caspase-3 and Fas-independent pathway. 1218 41

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.
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PMID:The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer cells. 1220 Jan 39

Inhibitor of apoptosis proteins (IAPs) interact with and inhibit caspases-3, -7, and -9. This interaction can be inhibited by Smac/DIABLO, a polypeptide released from mitochondria upon initiation of the apoptotic signaling process. Here we demonstrate that the first 4-8 N-terminal amino acids of Smac/DIABLO fused to the Drosophila antennapaedia penetratin sequence, a carrier peptide, enhance the induction of apoptosis and long term antiproliferative effects of diverse antineoplastic agents including paclitaxel, etoposide, 7-ethyl-10-hydroxycamptothecin (SN-38), and doxorubicin in MCF-7 breast cancer cells. Similar effects were observed in additional breast cancer and immortalized cholangiocyte cell lines. Further analysis demonstrated that the Smac-penetratin fusion peptide crossed the cellular membrane, bound XIAP and cIAP1, displaced caspase-3 from cytoplasmic aggregates, and enhanced drug-induced caspase action in situ. These studies demonstrate that inhibition of IAP proteins can modulate the efficacy of antineoplastic agents.
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PMID:Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ. 1221 61

Nutrient deprivation has been shown to cause cancer cell death. To exploit nutrient deprivation as anti-cancer therapy, we investigated the effects of the anti-metabolite 2-deoxy-D-glucose on breast cancer cells in vitro. This compound has been shown to inhibit glucose metabolism. Treatment of human breast cancer cell lines with 2-deoxy-D-glucose results in cessation of cell growth in a dose dependent manner. Cell viability as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide conversion assay and clonogenic survival are decreased with 2-deoxy-D-glucose treatment indicating that 2-deoxy-D-glucose causes breast cancer cell death. The cell death induced by 2-deoxy-D-glucose was found to be due to apoptosis as demonstrated by induction of caspase 3 activity and cleavage of poly (ADP-ribose) polymerase. Breast cancer cells treated with 2-deoxy-D-glucose express higher levels of Glut1 transporter protein as measured by Western blot analysis and have increased glucose uptake compared to non-treated breast cancer cells. From these results we conclude that 2-deoxy-D-glucose treatment causes death in human breast cancer cell lines by the activation of the apoptotic pathway. Our data suggest that breast cancer cells treated with 2-deoxy-D-glucose accelerate their own demise by initially expressing high levels of glucose transporter protein, which allows increased uptake of 2-deoxy-D-glucose, and subsequent induction of cell death. These data support the targeting of glucose metabolism as a site for chemotherapeutic intervention by agents such as 2-deoxy-D-glucose.
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PMID:Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death. 1223 67

To investigate the mechanisms underlying apoptosis in breast cancer cells, staurosporine was used as an apoptotic stimulus in the human breast cancer cell lines MCF-7 and T47D. Staurosporine induced dose and time dependent increases in DNA fragmentation which was abrogated by z-VAD-fmk. MCF-7 cells did not express caspase-3, suggesting that DNA fragmentation occurred in the absence of caspase-3 and that other caspases may be involved. Staurosporine induced DEVDase activity in T47D cells suggesting the involvement of caspase-3 and/or caspase-7, yet there was no DEVDase activity in MCF-7 cells, probably ruling out the involvement caspase-7. However, staurosporine induced the cleavage of pro-caspase-6 in MCF-7 cells, but not in T47D cells. Caspase dependent PARP cleavage was detected in MCF-7 cells at 3 h, whereas only partial PARP cleavage was detected in T47D cells and then only after 24 h. Moreover, staurosporine led to cytochrome c release at 2 h in MCF-7 cells and 6 h in T47D cells. In addition, a time dependent and caspase-independent reduction of the mitochondrial transmembrane potential was observed; which appeared to occur after the release of cytochrome c. Translocation of Bax from the cytosol to mitochondria was observed in both cell types, and this preceded cytochrome c release in both T47D and MCF-7 cells. Apoptotic events in both cell types differ temporally, involving activation of different caspases and mitochondrial changes.
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PMID:Apoptotic mechanisms in T47D and MCF-7 human breast cancer cells. 1237 8

Estrogen receptor (ER) has been a successful target for effective prevention and treatment strategies in breast cancer, whereas growth factors and their signaling molecules are proving to be effective treatment targets as well. Understanding the interaction between ER and growth factor signaling pathways should provide clues to optimal treatment approaches and new strategies to overcome and prevent endocrine resistance. Cross-talk between ER and signal transducer and activator of transcription 5 (Stat5) has also been reported. Stat5 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 have analyzed the role of Stat5 in the progression of ER-positive breast cancer cells such as T47D and MCF7 in which Stat5b is constitutively activated. Adenoviral-mediated dominant-negative Stat5 induced apoptosis in T47D cells but not in caspase-3 negative MCF7 cells. Our study indicates that targeting Stat5 may represent a new strategy to suppress estrogen receptor activity and induce apoptosis in Stat5-activated, ER-positive breast cancer.
Breast Cancer 2002
PMID:The role of Stat5 in estrogen receptor-positive breast cancer. 1245 12

Caspase-3 is a member of the cysteine protease family, which plays a crucial role in apoptotic pathways by cleaving a variety of key cellular proteins. Caspase-3 can be activated by diverse death-inducing signals, including the chemotherapeutic agents. The purpose of this study was to determine the levels of caspase-3 expression in breast tumor samples and to determine whether alterations in its expression can affect their ability to undergo apoptosis. Primary breast tumor and normal breast parenchyma samples were obtained from patients undergoing breast surgery and the expression of caspases-3 was studied. Similarly, normal mammary epithelial cells and several established mammary cancer cell lines were studied for caspases-3 expression by reverse transcriptase-polymerase chain reaction, Northern blot analysis, and Western blot analysis. Approximately 75% of the tumor as well as morphologically normal peritumoral tissue samples lacked the caspase-3 transcript and caspase-3 protein expression. In addition, the caspases-3 mRNA levels in commercially available total RNA samples from breast, ovarian, and cervical tumors were either undetectable (breast and cervical) or substantially decreased (ovarian). Despite the complete loss of caspase-3, the expression levels of other caspases, such as caspase-8 and caspase-9, were normal in all of the tumor samples studied. The sensitivity of caspase-3-deficient breast cancer (MCF-7) cells to undergo apoptosis in response to doxorubicin and other apoptotic stimuli could be augmented by reconstituting caspase-3 expression. These results suggest that the loss of caspases-3 expression may represent an important cell survival mechanism in breast cancer patients.
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PMID:Down-regulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance. 1248 36

ARHI, an imprinted putative tumor suppressor gene, encodes a M(r) 26,000 GTP-binding protein that is 60% homologous to ras and rap but has a dramatically different function. ARHI expression is down-regulated in a majority of breast and ovarian cancers. Using a dual adenovirus system, we have reexpressed ARHI in ovarian cancer and breast cancer cells that have lost ARHI expression. Reexpression of ARHI inhibited growth, decreased invasiveness, and induced apoptosis. At 5 days after infection with ARHI adenovirus, 30-45% of MDA-MB-231 breast cancer cells and 5-11% of SKOv3 ovarian cancer cells were apoptotic as judged by a terminal deoxynucleotidyl transferase-mediated nick end labeling assay and by Annexin V staining with flow cytometric analysis. Although poly(ADP-ribose) polymerase could be detected immunohistochemically in the nuclei of apoptotic cells, no activation of the effector caspases (caspase 3, 6, 7, or 12) or the initiator caspases (caspase 8 or 9) could be detected in cell lysates using Western blotting. When gene expression was analyzed on a custom cDNA array that contained 2304 known genes, infection with ARHI adenovirus up-regulated 15 genes relative to control cells infected with LacZ adenovirus. The greatest degree of mRNA up-regulation was observed in a Homo sapiens calpain-like protease. On Western blot analysis, calpain protein was increased 2-3-fold at 3-5 days after infection with ARHI adenovirus. No increase in calpain protein was observed after LacZ adenovirus infection. Calpain cleavage could be detected after ARHI reexpression, and inhibitors of calpain, but not inhibitors of caspase, partially prevented ARHI-induced apoptosis. Consequently, reexpression of ARHI in breast and ovarian cancer cells appears to induce apoptosis through a caspase-independent, calpain-dependent mechanism.
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PMID:Reexpression of the tumor suppressor gene ARHI induces apoptosis in ovarian and breast cancer cells through a caspase-independent calpain-dependent pathway. 1249 68

NuMA is a nuclear matrix protein that has an essential function in the organization of the mitotic spindle. Here we have studied the fate of NuMA in Fas-treated apoptotic Jurkat T and HeLa cells. We show that in both cell lines NuMA is an early target protein for caspases and that NuMA is cleaved coincidently with poly(ADP-ribose) polymerase-1 (PARP-1) and nuclear lamin B. NuMA is cleaved differently in Jurkat T and HeLa cells, suggesting that different sets of caspases are activated in these cell lines. The normal diffuse intranuclear distribution of NuMA changed during apoptosis: first NuMA condensed, then concentrated in the center of the nucleus and finally encircled the nuclear fragments within the apoptotic bodies. NuMA seems to be preferentially cleaved by caspase-3 in vivo since it was not cleaved in staurosporine-treated caspase-3-null MCF-7 breast cancer cells. The cleavage of NuMA, lamin B and PARP-1 was inhibited in the presence of three different caspase inhibitors: z-DEVD-FMK, z-VEID-FMK and z-IETD-FMK. Furthermore, in the presence of caspase inhibitors approximately 5-10% of the cells showed atypical apoptotic morphology. These cells had convoluted nuclei, altered chromatin structure and additionally, they were negative for NuMA and lamins. Since caspase-8, -3 and -7 were not activated and PARP was not cleaved in these cells as judged by western blotting and immunofluorescence studies, it is likely that this is an atypical form of programmed cell death owing to a proteinase(s) independent of caspases. These results characterize the role of NuMA in programmed cell death and suggest that cleavage of NuMA plays a role in apoptotic nuclear breakdown.
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PMID:NuMA and nuclear lamins behave differently in Fas-mediated apoptosis. 1250 17


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