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)

Immunohistochemical analysis of the apoptosis-effector protease CPP32 (Caspase-3) in normal lymph nodes, tonsils, and nodes affected with reactive hyperplasia (n = 22) showed strong immunoreactivity in the apoptosis-prone germinal center B-lymphocytes of secondary follicles, but little or no reactivity in the surrounding long-lived mantle zone lymphocytes. Immunoblot analysis of fluorescence-activated cell sorted germinal center and mantle zone B cells supported the immunohistochemical results. In 22 of 27 (81%) follicular small cleaved cell non-Hodgkin's B-cell lymphomas, the CPP32-immunopositive germinal center lymphocytes were replaced by CPP32-negative tumor cells. In contrast, the large cell component of follicular mixed cells (FMs) and follicular large cell lymphomas (FLCLs) was strongly CPP32 immunopositive in 12 of 17 (71%) and in 8 of 14 (57%) cases, respectively, whereas the residual small-cleaved cells were poorly stained for CPP32 in all FLCLs and in 12 of 17 (71%) FMs, suggesting that an upregulation of CPP32 immunoreactivity occurred during progression. Similarly, cytosolic immunostaining for CPP32 was present in 10 of 12 (83%) diffuse large cell lymphomas (DLCLs) and 2 of 3 diffuse mixed B-cell lymphomas (DMs). Immunopositivity for CPP32 was also found in the majority of other types of non-Hodgkin's lymphomas studied. Plasmacytomas were CPP32 immunonegative in 4 of 12 (33%) cases, in contrast to normal plasma cells, which uniformly contained intense CPP32 immunoreactivity, implying downregulation of CPP32 in a subset of these malignancies. All 12 peripheral blood B-cell chronic lymphocyte leukemia specimens examined were CPP32 immunopositive, whereas 3 of 3 small lymphocytic lymphomas were CPP32 negative, suggesting that CPP32 expression may vary depending on the tissue compartment in which these neoplastic B cells reside. The results show dynamic regulation of CPP32 expression in normal and malignant lymphocytes.
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PMID:Immunolocalization of the ICE/Ced-3-family protease, CPP32 (Caspase-3), in non-Hodgkin's lymphomas, chronic lymphocytic leukemias, and reactive lymph nodes. 916 Jun 89

T lymphocytes recognizing tumor antigens eventually undergo anergy or Fas-mediated death. V gamma9/V delta2+ T cells recognize poorly characterized ligand moieties on human B-cell lymphomas. Here we show that gammadelta T cells, a model for the study of activation-induced apoptosis, activate on repeated in vitro antigen-recognition caspase 3 and 8 and dramatically down-regulate their cytotoxic and secretory function. Caspase hindrance enhanced gammadelta T cell survival and sustained the killing of neoplastic cells and the release of IFN-gamma and tumor necrosis factor alpha. Caspases of tumor-specific T cells represent a candidate target to complement adoptive immunotherapy strategies.
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PMID:Inhibition of caspases maintains the antineoplastic function of gammadelta T cells repeatedly challenged with lymphoma cells. 1130 92

In vitro studies indicate that in lymphomas, execution of apoptosis involves activation of effector caspases. To investigate activation of effector caspases in vivo in biopsy specimens of lymphomas, a new assay was developed using antibodies against active caspase 3 and p89, a protein fragment generated by caspase-specific cleavage of poly-ADP ribose polymerase (PARP). Using this assay, it was found that in B-cell lymphomas, levels of active caspase 3/p89-positive cells correlate strongly with morphologically recognizable apoptotic cells. The number of active caspase 3/p89-positive cells was low in follicular lymphomas and usually high in diffuse large cell lymphomas. Highest numbers were found in Burkitt lymphomas and in two biopsies of diffuse large B-cell lymphomas (DLCLs) obtained several days after initiation of therapy. It is concluded that apoptosis in reactive lymphoid tissues and in B-cell lymphomas always involves activation of effector caspase 3 and cleavage of one of the major effector caspase substrates, PARP-1. Moreover, levels of effector caspase activation are constantly low in low-grade follicular lymphomas and vary considerably in DLCL and Burkitt lymphoma.
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PMID:Apoptosis in B-cell lymphomas and reactive lymphoid tissues always involves activation of caspase 3 as determined by a new in situ detection method. 1185 94

We have reviewed the clinical, morphologic, immunophenotypical, and molecular features of a series of 27 cases of nodal marginal zone lymphoma with the aim of defining this entity more precisely. The series was characterized by a relatively favorable clinical course, with a low clinical stage at diagnosis (59% patients with clinical stage I-II) and a 5-year overall survival probability of 79%. However, the disease persisted in a relatively large fraction of the patients, thus yielding a 5-year failure-free survival probability of 22%. Molecular and immunohistochemical analyses of the series revealed heterogeneity in the frequency of IgV(H) somatic mutation and in the expression of IgD, CD43, MUM1, and CD38. Apart from the absence of nuclear Bcl10, no clear distinction could be made from the expression profiling of other B-cell lymphomas claimed to be derived from marginal zone B cells. Additionally, the immunophenotype of the tumoral cells in all cases but one differed from that described in monocytoid B cells. It was characterized by a Bcl2-, p21+, cyclin E+ profile. The analysis of apoptosis-regulator proteins disclosed abnormalities in the expression of survivin and active caspase 3, which could partially explain the abnormal regulation of apoptosis observed in these tumors. Molecular and immunohistochemical data obtained in this study strongly imply that there is significant heterogeneity among the cases included in the category termed nodal marginal zone lymphoma.
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PMID:Nodal marginal zone lymphoma: a heterogeneous tumor: a comprehensive analysis of a series of 27 cases. 1276 79

The purpose of the present paper was to examine the level of apoptosis and the relationships among apoptosis, apoptosis-associated proteins, and proliferating potential in lymphoma tissues to clarify the characteristics of apoptosis in diffuse large B-cell lymphomas (DLBCL) of the central nervous system (CNS). The formalin-fixed, paraffin-embedded tissues of CNS and non-CNS DLBCL (20 cases each) were studied by terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) and immunohistochemistry, using antibodies against single-stranded DNA (ssDNA), cleaved caspase-3, bcl-2, bax, p53, Fas and Ki-67. The cleaved caspase-3 immunohistochemistry detected apoptosis of the lymphoma cells most sensitively compared to TUNEL and ssDNA immunohistochemistry. High expression (grade + + or + + +) of cleaved caspase-3 was found more frequently in CNS DLBCL (11 cases, 55%) than non-CNS DLBCL (three cases, 15%; P = 0.009). Bax-positivity of lymphoma cells was increased in six cases of CNS DLBCL, which also showed high positivity of cleaved caspase-3. There was no significant correlation between the cleaved caspase-3-positivity and the Ki-67 positivity. The present study indicates that the number of apoptotic cells and expression level of cleaved caspase-3 were significantly higher in CNS DLBCL than non-CNS DLBCL, and that the correlation of bax and cleaved caspase-3 expression was often present in CNS DLBCL.
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PMID:Immunohistochemical analysis of cleaved caspase-3 detects high level of apoptosis frequently in diffuse large B-cell lymphomas of the central nervous system. 1574 20

Ocular adnexa B-cell lymphomas are a relatively rare group of extranodal lymphomas, marginal-zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas) being the most frequent type at this location. As with other nongastrointestinal MALT lymphomas, ocular adnexa MALT lymphomas have distinct characteristics from those of the gastric MALT model, implying specific pathogenic events, which could be of interest in the prediction of clinical behavior and the choice between therapeutic options. In a series of 39 cases of ocular adnexa MALT lymphomas, studied using a tissue microarray, we observed that the most frequent alteration was related to apoptosis regulation. Thus, caspase 3 activity was completely abolished, and phosphorylated IkappaBalpha, a marker of NF-kappaB activation, showed increased expression, while cases with an increased number of large cells displayed increased expression of survivin and other cell-cycle-related proteins, such as cyclin A, cyclin E and Ki67, and p16 expression was reduced. There were no occurrences of t(11;18)(q21,q21), while 5/37 cases exhibited t(14;18)(q32;q21). Aberrant nuclear expression of bcl10 was observed in 11 cases, independently of the presence of translocations, and was significantly associated with phosphorylated IkappaBalpha expression and a reduced TdT-mediated biotin-dUTP nicked-end labeling apoptotic index. Moreover, patients with tumoral bcl10 nuclear expression showed shorter failure-free survival.
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PMID:Nuclear bcl10 expression characterizes a group of ocular adnexa MALT lymphomas with shorter failure-free survival. 1664 71

Lym-1 was one of the first antibodies to be used successfully for the radioimmunotherapy of the human malignant lymphomas. This antibody, which recognizes the HLA-DR10 antigen preferentially expressed in B-cell lymphomas, was recently shown to induce apoptosis upon binding to lymphoma cells. In this study, Lym-1-induced apoptosis was studied to identify the potential molecular pathways of programmed cell death and to demonstrate the clinical potential of this antibody in the treatment of the human malignant lymphomas. Immunofluorescence microscopy revealed that Lym-1 stained focal areas of the cell surface, consistent with the fact that the HLA-DR10 antigen is associated with lipid rafts, a known prerequisite for apoptosis signaling. Likewise, Annexin V/propidium iodide staining and TUNEL assays demonstrated that both murine Lym-1 and chimeric Lym-1 induced both early and late apoptosis, respectively, unlike anti-CD20 rituximab. Furthermore, Lym-1 was found to produce a rapid loss of mitochondrial membrane potential and mitochondrial release of cytochrome C 14 hours post-Lym-1 treatment. Although it was found to activate caspase-3, inhibitors of caspase pathways showed that the Lym-1-induced apoptosis in lymphoma cell lines is independent of caspase induction. Finally, treatment studies in vivo demonstrated that, compared with murine anti-CD20 (2B8), Lym-1 was more effective in inducing the regression of human lymphoma xenografts. Based upon these results, chimeric Lym-1 should be especially effective in treating lymphoma patients, as, in addition to being able to elicit immune effector functions such as chimeric anti-CD20, it can also induce apoptosis directly upon cell binding.
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PMID:Lym-1-induced apoptosis of non-Hodgkin's lymphomas produces regression of transplanted tumors. 1765 Oct 40

Clinical outcome in patients with primary nodal diffuse large B-cell lymphomas (DLBCLs) is correlated with expression of inhibitors of the intrinsic apoptosis pathway, including X-linked inhibitor of apoptosis protein (XIAP). XIAP suppresses apoptosis through inhibiting active caspase-3, caspase-7, and caspase-9. In this study, we investigated to see if the small-molecule XIAP antagonist 1396-12 induces cell death in cultured lymphoma cells of patients with DLBCL. Treatment with this XIAP antagonist resulted in relief of caspase-3 inhibition and in induction of apoptosis in 16 of 20 tested DLBCL samples. Sensitivity to the XIAP antagonist was observed in both chemotherapy-refractory and -responsive DLBCL, but did not affect peripheral blood mononuclear cells and tonsil germinal-center B cells from healthy donors. XIAP antagonist-sensitive samples were characterized by high expression levels of XIAP, relatively low expression levels of Bcl-2, and by constitutive caspase-9 activation. These data indicate that the small-molecule XIAP antagonist can induce apoptosis in cultured DLBCL cells and therefore should be considered for possible development as a therapy for these patients. In vitro sensitivity to the XIAP antagonist can be predicted based on biological markers, suggesting the possibility of predefining patients most likely to benefit from XIAP antagonist therapy.
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PMID:Small-molecule XIAP antagonist restores caspase-9 mediated apoptosis in XIAP-positive diffuse large B-cell lymphoma cells. 1791 49

Burkitt's lymphoma and atypical Burkitt/Burkitt-like lymphoma (BL/BLL) are considered highly aggressive B-cell lymphomas with a rapid proliferative rate and high rate of apoptosis. The aim of the present study was to confirm whether apoptotic and cell proliferative factors affect BL/BLL clinical outcomes. We retrospectively analyzed the relationship between the clinical and immunophenotypic features of 43 BL/BLL patients by immunohistochemical staining for bcl-2 and double staining for Ki-67 plus caspase-3. In double staining experiments, all patients were divided into high and low groups for the expression of caspase-3, Ki-67, and both Ki-67 and caspase-3, by using the medians of their percentages as limits. The 43 BL/BLL patients were divided into high caspase-3 (n = 19) and low caspase-3 (n = 24) groups. There was a significant difference in the overall survival between the high (77%) and low caspase-3 (33%) groups; the survival rate of patients in the low caspase-3 group who received aggressive short-term chemotherapy (58%) was significantly better than that of patients who received cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) therapy (17%). All patients positive for bcl-2 were in the low caspase-3 group (high caspase-3 group, 0%; low caspase-3 group, 42%). The overall survival tended to be better in the high caspase-3 and bcl-2-negative group (76%) than in the low caspase-3 and bcl-2-negative (50%) group. In addition, the low caspase-3 and bcl-2-positive group tended to show the worst prognosis (16%). We suggest that caspase-3 may function as an indicator of the prognosis of BL/BLL. Furthermore, intensive short-term chemotherapeutic regimens may improve the prognosis of the patients in the low caspase-3 group.
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PMID:Estimation of the relationship between caspase-3 expression and clinical outcome of Burkitt's and Burkitt-like lymphoma. 1875 67

Rituximab is the first line drug to treat non Hodgkin's lymphoma (B-NHL) alone or in combination with chemotherapy. However, 30-40% of B-NHL patients are unresponsive to rituximab or resistant after therapy. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of PEBP family and functions as an anti-apoptotic molecule. In this study, we found hPEBP4 to be expressed in up to 90% of B-cell lymphoma patients, but in only 16.7% of normal lymph nodes. Interestingly, hPEBP4 overexpression inhibited rituximab-mediated complement dependent cytotoxicity (R-CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in B-NHL cells while downregulation of hPEBP4 augmented the therapeutic efficacy of rituximab both in vitro and in vivo. Furthermore, hPEBP4 silencing sensitized the primary B-acute lymphocytic leukemia (B-ALL) cells to R-CDC. During rituximab-mediated complement dependent cytotoxicity, hPEBP4 was recruited to the cell membrane in a PE-binding domain dependent manner and inhibited R-CDC induced calcium flux and reactive oxygen species (ROS) generation. These events contributed to the decrease of cell death induced by R-CDC in B-cell lymphomas. Meanwhile, hPEBP4 knockdown potentiated the chemosensitization of the rituximab in B-cell lymphoma cells by regulating the expression of Bcl-xl, Cycline E, p21(waf/cip1) and p53 and the activation of caspase-3 and caspase-9. Considering that hPEBP4 conferred cellular resistance to rituximab treatment and was preferentially expressed in lymphoma tissue, it could be a potential valuable target for adjuvant therapy for B-cell lymphoma.
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PMID:Silencing of human phosphatidylethanolamine-binding protein 4 enhances rituximab-induced death and chemosensitization in B-cell lymphoma. 2345 Oct 95


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