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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro studies suggest that resistance to chemotherapy-induced apoptosis might explain poor response to therapy in fatal cases. Actual execution of apoptosis depends on proper functioning of effector caspases, particularly caspase 3, and on the expression levels of apoptosis-regulating proteins, including Bcl-2 and the recently identified granzyme B- specific protease inhibitor 9 (PI9). Thus, high levels of caspase 3 activation should reflect proper functioning of the apoptosis pathways, resulting in chemotherapy-sensitive neoplastic cells and a favorable prognosis. We tested this hypothesis by quantifying numbers of tumor cells positive for active caspase 3, Bcl-2, and PI9, respectively, in pretreatment biopsies of systemic anaplastic large cell lymphoma (ALCL) patients and by comparing these numbers with clinical outcome. Activation of caspase 3 in more than 5% of the tumor cells was strongly correlated with a highly favorable outcome. High numbers of Bcl-2- and PI9-positive tumor cells were found to predict unfavorable prognosis. This prognostic effect was strongly related to anaplastic lymphoma kinase (ALK) status: ALK-positive ALCL had significantly higher levels of active caspase 3, while high expression of the antiapoptotic proteins Bcl-2 and PI9 was almost completely restricted to ALK-negative cases. In conclusion, high numbers of active caspase 3-positive tumor cells predict a highly favorable prognosis in systemic ALCL patients. Poor prognosis is strongly related to high numbers of Bcl-2- and PI9-positive neoplastic cells. These data support the notion that a favorable response to chemotherapy depends on an intact apoptosis cascade. Moreover, these data indicate that differences in prognosis between ALK-positive and ALK-negative ALCL might be explained by differences in expression of apoptosis-inhibiting proteins.
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PMID:Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma. 1203 86

Anaplastic large cell lymphoma (ALCL) can be divided into two major groups. The first is a spectrum of CD30+ T-cell lymphoproliferative disorders including primary cutaneous ALCL and lymphomatoid papulosis, usually affecting older patients but characterized by an excellent prognosis. The second is systemic nodal ALCL, which on the basis of genetic and immunophenotypic features combined with clinical parameters can be divided into two subgroups: anaplastic lymphoma kinase (ALK)-positive and ALK-negative systemic ALCL. ALK expression, usually the result of a t(2;5) translocation, correlates with the expression of other markers such as EMA and a cytotoxic phenotype, and is strongly related to younger age groups, lower international prognostic index (IPI) risk groups, and a good prognosis. ALK-negative ALCL, however, shows a more heterogeneous immunophenotype and clinical behaviour, and prognostic parameters are needed to determine treatment strategies in individual patients. Besides clinical parameters included in the IPI, recent studies have pointed out several biological prognosticators of potential value, such as the percentage of tumour-infiltrating activated cytotoxic T-lymphocytes. The expression of proteins involved in the execution or regulation of apoptosis, such as activated caspase 3, Bcl-2, and PI9, was also found to be strongly related to clinical outcome. These studies indicate that inhibition of the apoptosis cascade in particular is an important mechanism that can explain the poor clinical outcome in therapy refractory ALCL. Functional studies are required to investigate whether disruption of one or more of the apoptosis pathways is the major factor in the fatal outcome of the disease and whether apoptosis resistance based on inhibition of one pathway can be overcome by activating another pathway that is still intact.
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PMID:ALK-negative systemic anaplastic large cell lymphoma: differential diagnostic and prognostic aspects--a review. 1269 35

Signal transducer and activator of transcription 3 (STAT3), normally activated by Janus kinase (JAK) in response to cytokine stimulation, has been shown to have oncogenic potential. In addition to JAK, recent data suggest that STAT3 can also be activated by other proteins such as the aberrant fusion protein, NPM-ALK, which is expressed in a subset of systemic anaplastic large cell lymphoma (ALCL). In this study, we investigated the possible role of JAK in activating STAT3 in ALCL using two ALK-positive ALCL cell lines, Karpas 299 and SU-DHL-1. At the steady state, JAK3 showed detectable tyrosine phosphorylation by immunoprecipitation. Treatment with AG490, a JAK inhibitor, decreased but did not completely abrogate tyrosine phosphorylation of JAK3 and STAT3 in a concentration-dependent manner. Similar results were obtained using two other inhibitors of JAK3, WHI-P131 and WHI-P154. These biochemical changes were associated with apoptosis in both cell lines that was coupled with activation of caspase 3 and decreased bcl-xL and bcl-2. Cell cycle analysis revealed a decrease in the S phase, which may be attributed to cyclin D3 downregulation and p21(waf1) upregulation. Importantly, the tyrosine kinase activity of NPM-ALK, as assessed by an in vitro assay, decreased with increasing concentrations of AG490. Our findings highlight the importance of JAK3 in activating STAT3 in ALCL, and that NPM-ALK-mediated activation of STAT3 is influenced by the functional status of JAK3.
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PMID:Inhibition of JAK3 induces apoptosis and decreases anaplastic lymphoma kinase activity in anaplastic large cell lymphoma. 1293 99

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is an aberrant fusion gene product expressed in a subset of cases of anaplastic large cell lymphoma (ALCL). It has been shown that NPM-ALK binds to and activates signal transducer and activator of transcription 3 (STAT3) in vitro, and that STAT3 is constitutively active in ALK(+) ALCL cell lines and tumors. In view of the oncogenic potential of STAT3, we further examined its biological significance in ALCL using two ALK(+) ALCL cell lines (Karpas 299 and SU-DHL-1) and an adenoviral vector that carries dominant-negative STAT3 (AdSTAT3DN). Infection by AdSTAT3DN led to the expression of STAT3DN in both ALK(+) ALCL cell lines at a similar efficiency. Subcellular fractionation studies showed that a significant proportion of the expressed STAT3DN protein translocated to the nucleus, despite the fact that STAT3DN has a mutation at residue 705(tyrosine --> phenylalanine), a site that is believed to be crucial for STAT3 activation and nuclear translocation. Introduction of STAT3DN induced apoptosis and G(1) cell cycle arrest. Western blot studies showed that expression of STAT3DN resulted in caspase-3 cleavage, downregulation of Bcl-2, Bcl-xL, cyclin D3, survivin, Mcl-1, c-Myc and suppressor of cytokine signaling 3. These results support the concept that STAT3 activation is pathogenetically important in ALCL cells by deregulating the expression of multiple target proteins that are involved in the control of apoptosis and cell cycle progression.
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PMID:Selective inhibition of STAT3 induces apoptosis and G(1) cell cycle arrest in ALK-positive anaplastic large cell lymphoma. 1518 87

Expression of the cytokine receptor CD30 is a characteristic feature of anaplastic large cell lymphoma (ALCL). Reports regarding CD30-mediated signaling in ALCL cells are highly controversial, especially with respect to the regulation of cell survival. In this study, we stimulated 6 ALCL-derived cell lines with immobilized anti-CD30 antibody. CD30-induced cell death was investigated by Western blot and FACS analysis. CD30-dependent cell proliferation and activation was analyzed by applying the trypan blue exclusion method and a luciferase-based ATP assay. The expression of cell cycle relevant proteins and the activation of mitogen-activated protein (MAP) kinases were also examined. We demonstrated that activation of CD30 did not lead to the cleavage of pro-caspase-3. FACS analysis confirmed that in all examined cells cell death was not mediated by CD30. Cell growth was strongly inhibited in 2 of the 6 cell lines and restrained cell growth was accompanied by expression of the cell cycle inhibitor p21(WAF1/CIP1). Furthermore, stimulation of CD30 led to the activation of the p38 MAP kinase but not of the extracellular signal-regulated kinase (ERK) or the jun N-terminal kinase (JNK). Interestingly, activation of CD30 induced a strong synergistic reduction of cell activity, if the p38 MAP kinase activity was blocked by SB203580. The aim of the study was to elucidate CD30-induced signaling in different ALCL-cells. Our results suggest that CD30-mediated apoptosis is not a common feature in this cell type and that p38 MAP kinase is involved in CD30-mediated singal transduction.
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PMID:Signal transduction in anaplastic large cell lymphoma cells (ALCL) mediated by the tumor necrosis factor receptor CD30. 1529 61

In this study, the expression of activated caspase-3 by the tumor cells of classical Hodgkin lymphoma (cHL), the Hodgkin-Reed-Sternberg (HRS) cells, is confirmed. This raises the question why caspase-3 does not kill HRS cells. There are only a few molecules, which are able to directly inhibit caspase-3. One of them is cIAP2. We show that cIAP2 is expressed in the HRS cells in 20 of 23 cHL cases by in situ hybridization. Suppression experiments with cIAP2 antisense RNA show that down-regulation of cIAP2 significantly reduces apoptosis resistance in cHL cell lines. cIAP2 overexpression appears to be unique for HRS cells since the tumor cells of non-Hodgkin lymphomas are nearly cIAP2-negative. We demonstrate that cIAP2 is inducible by CD30 stimulation in cHL cell lines of T-cell origin and anaplastic large cell lymphoma cell lines, whereas cHL cell lines of B-cell origin constitutively express cIAP2. Inhibition of cIAP2 expression by cIAP2 antisense RNA decreases resistance to apoptosis. The results indicate that cIAP2 contributes to the apoptosis resistance of HRS cells, mainly by inhibiting effector caspases. According to these findings, a therapeutical application of inhibitors of apoptosis proteins antagonists in cHL appears promising.
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PMID:cIAP2 is highly expressed in Hodgkin-Reed-Sternberg cells and inhibits apoptosis by interfering with constitutively active caspase-3. 1630 85

Anaplastic large cell lymphoma (ALCL) includes a subset of tumors that has abnormalities of chromosome 2p23, resulting in overexpression of anaplastic lymphoma kinase (ALK). Previous studies have reported differences in apoptotic rate and expression levels of apoptosis regulatory proteins between ALK+ and ALK- ALCL. In this study, we assessed for expression of the intrinsic apoptotic pathway proteins cytochrome c, apoptosis protease-activating factor 1, and procaspase 9 in 2 ALK+ ALCL cell lines and 42 ALCL tumors (17 ALK+, 25 ALK-). We used the Karpas 299 and SU-DHL-1 cell lines, and the inhibitors Z-LEHD-FMK (specific for caspase 9) and Boc-D-FMK (general caspase inhibitor) to investigate the role of caspase 9 activation in chemotherapy-induced apoptotic cell death. Caspase 9 activity was significantly increased in Karpas-299 and SU-DHL-1 cells after chemotherapy treatment, but remained as low as control levels with addition of either caspase inhibitor. Both caspase inhibitors rescued a substantial fraction of Karpas 299 and SU-DHL-1 cells from drug-induced cell death. In ALCL tumors, expression of cytochrome c, apoptosis protease-activating factor 1, and procaspase 9 was also assessed and correlated with apoptotic rate and activated caspase 3 levels. Cytochrome c was expressed in all 13 (100%) ALK+ and 18 (95%) of 19 ALK- ALCL tumors. Apoptosis protease-activating factor 1 was detected in 14 (88%) of 16 ALK+ and 19 (79%) of 24 ALK- ALCL tumors. Procaspase 9 was expressed in 5 (30%) of 17 ALK+ and 2 (8%) of 25 ALK- ALCL tumors (P = .09). In the entire study group (ALK+ and ALK- ALCL), procaspase 9 expression levels significantly correlated with apoptotic rate (P = .02) and activated caspase 3 levels (P = .05). This correlation could not be shown in the ALK+ or ALK- ALCL subgroups, presumably because of the small sample size. In conclusion, chemotherapy-induced cell death in ALK+ ALCL cells involves the intrinsic apoptotic pathway, and apoptosome function may be an important determinant of apoptosis in ALCL tumors.
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PMID:Intrinsic apoptotic pathway in anaplastic large cell lymphoma. 1678 88

JSI-124 (cucurbitacin I) has been recently described as a specific inhibitor of signal transducer and activator of transcription-3 (STAT3). As STAT3 activation is pathogenetically important in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL), we investigated whether JSI-124 can mediate significant inhibitory effects in this cell type. In two ALK+ ALCL cell lines (Karpas 299 and SU-DHL-1), JSI-124 significantly reduced the number of viable cells to 50% of that of negative controls at a dose of 5-10 micromol/l at 24 h and 1-1.25 micromol/l at 48 h. This decrease in viability was associated with apoptosis, as confirmed by the increase in the subG(0/1) fraction, poly(ADP-ribose)polymerase cleavage and expression of active caspase 3. JSI-124 decreased the phosphorylated-STAT3 and -Janus kinase-3 (JAK3) levels in a dose-dependent fashion, and these changes were coupled with significant decreases in several STAT3 downstream targets, including mcl-1, bcl-2, bcl-xL and cyclin D3. Interestingly, JSI-124 also dramatically decreased the protein levels of JAK3 and nucleophosmin (NPM)-ALK, and these effects were reversible by MG132. Our data support that JSI-124 is a potentially useful therapeutic agent for ALK+ ALCL. In addition to its role as a tyrosine kinase inhibitor, JSI-124 appears to be involved in regulating proteosome degradation for proteins such as JAK3 and NPM-ALK.
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PMID:JSI-124 (cucurbitacin I) inhibits Janus kinase-3/signal transducer and activator of transcription-3 signalling, downregulates nucleophosmin-anaplastic lymphoma kinase (ALK), and induces apoptosis in ALK-positive anaplastic large cell lymphoma cells. 1693 98

The molecular chaperone heat shock protein 90 (Hsp90) affects the function of many oncogenic signaling proteins including nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressed in anaplastic large cell lymphoma (ALCL). While ALK-positive ALCL cells are sensitive to the Hsp90 inhibitor and the geldanamycin (GA) analog, 17-allylamino-17-demethoxygeldanamycin (17-AAG), the proteomic effects of these drugs on ALK-positive ALCL cells are unpublished. In this study, we investigated the cellular, biologic, and proteomic changes occurring in ALK-positive ALCL cells in response to GA treatment. GA induced G2/M cell cycle arrest and caspase-3-mediated apoptosis. Furthermore, quantitative proteomic changes analyzed by cleavable isotope-coded affinity tag-LC-MS/MS (cICAT-LC-MS/MS) identified 176 differentially expressed proteins. Out of these, 49 were upregulated 1.5-fold or greater and 70 were downregulated 1.5-fold or greater in GA-treated cells. Analysis of biological functions of differentially expressed proteins revealed diverse changes, including induction of proteins involved in the 26S proteasome as well as downregulation of proteins involved in signal transduction and protein and nucleic acid metabolism. Pathway analysis revealed changes in MAPK, WNT, NF-kappaB, TGFbeta, PPAR, and integrin signaling components. Our studies reveal some of the molecular and proteomic consequences of Hsp90 inhibition in ALK-positive ALCL cells and provide novel insights into the mechanisms of its diverse cellular effects.
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PMID:Proteome-wide changes induced by the Hsp90 inhibitor, geldanamycin in anaplastic large cell lymphoma cells. 1761 Feb 8

p53 is expressed frequently, but is rarely mutated in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) tumours. Nutlin-3a is a recently developed small molecule that targets Mdm2, a critical negative regulator of p53, and disrupts the p53-Mdm2 interaction resulting in p53 stabilization and activation. We show that nutlin-3a activates p53 in ALK+ ALCL cells carrying a wild type (wt) or mutated but partially functional p53 gene resulting in p53-dependent cell-cycle arrest and apoptosis. Cell-cycle arrest was associated with upregulation of the cyclin-dependent kinase inhibitor p21. Nutlin-3a-induced apoptotic cell death was accompanied by Bax and Puma upregulation, downregulation of Bcl-xl, survivin, and caspase-3 cleavage, and this was reduced when p53-dependent transactivation activity was inhibited by pifithrin-alpha, or when pifithrin-mu was used to inhibit direct p53 targeting of mitochondria. Nutlin-3a sensitized the activation of the extrinsic apoptotic pathway in wt-p53 ALK+ ALCL cells, in part, through upregulation of DR-5 and downregulation of c-Flip(S/L), and was synergistic with TRAIL in cell death induction. In addition, nutlin-3a treatment enhanced doxorubicin cytotoxicity against ALK+ ALCL cells harbouring mt p53, and this was associated with p73 upregulation. These data suggest that disruption of the p53-mdm2 interaction by nutlin-3a offers a novel therapeutic approach for ALK+ ALCL patients.
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PMID:The therapeutic potential of p53 reactivation by nutlin-3a in ALK+ anaplastic large cell lymphoma with wild-type or mutated p53. 1974 26


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