Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The induction of apoptosis of tumor cells by the colonic fermentation product butyrate is thought to be an important mechanism in protection against colorectal cancer. Because a major action of butyrate is to inhibit histone deacetylase (leading to chromatin relaxation and altered gene expression), butyrate may induce apoptosis by derepression of specific cell death genes. Here we show that butyrate and trichostatin A (a more selective inhibitor of histone deacetylase) induce the same program of apoptosis in Jurkat lymphoid and LIM 1215 colorectal cancer cell lines that is strictly dependent on new protein synthesis (within 10 h) and that leads to the conversion of the proenzyme form of caspase-3 to the catalytically active effector protease (within 16 h) and apoptotic death (within 24 h). Cells primed with a low concentration of butyrate that itself did not induce activation of caspase-3 or apoptosis were, nevertheless, rendered highly susceptible to induction of apoptosis by staurosporine (an agent that has recently been shown to act by causing mitochondrial release of cytochrome c). Synergy between butyrate and staurosporine was due to the presence of a factor in the cytosol of butyrate-primed cells which enhanced over 7-fold the activation of caspase-3 induced by the addition of cytochrome c and dATP to isolated cytosol. We propose that changes at the level of chromatin structure, induced by a physiological substance butyrate, lead to the expression of a protein that facilitates the pathway by which mitochondria activate caspase-3 and trigger apoptotic death of lymphoid and colorectal cancer cells.
Cancer Res 1997 Sep 01
PMID:Induction of caspase-3 protease activity and apoptosis by butyrate and trichostatin A (inhibitors of histone deacetylase): dependence on protein synthesis and synergy with a mitochondrial/cytochrome c-dependent pathway. 928 76

Recent work has demonstrated that glucocorticoids, nucleoside analogues, and other cancer chemotherapeutics induce apoptosis in chronic lymphocytic leukemia (CLL) cells. In this study, we investigated the involvement of protease activation in these responses using selective peptide inhibitors of the interleukin-1beta converting enzyme (ICE)/caspase family and a Ca2+-activated protease we recently implicated in thymocyte apoptosis. Apoptosis was associated with proteolytic cleavage of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) and increased caspase protease activity, and cell-permeant caspase antagonists [zVAD(OMe)fmk and Boc-D(OBzl)cmk] blocked apoptosis in response to the glucocorticoid methylprednisolone or the nucleoside analogue fludarabine, indicating that caspase activation was required for these responses. However, a peptide-based inhibitor of the Ca2+-dependent lamin protease (zAPFcmk) also completely suppressed DNA fragmentation and the cleavage of lamin B1 . Strikingly, treatment of cells with zAPFcmk alone led to characteristic PARP cleavage, depletion of the precursor forms of two ICE family proteases (CPP32 and ICH-1), and phosphatidylserine exposure, suggesting that blockade of the lamin protease led to activation of the ICE family. Our results implicate the lamin protease as a target for Ca2+ during chemotherapy-induced apoptosis in CLL lymphocytes, and they identify a novel functional interaction between the protease and members of the ICE family.
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PMID:Protease activation is required for glucocorticoid-induced apoptosis in chronic lymphocytic leukemic lymphocytes. 934 52

Betulinic acid (BA), a melanoma-specific cytotoxic agent, induced apoptosis in neuroectodermal tumors, such as neuroblastoma, medulloblastoma, and Ewing's sarcoma, representing the most common solid tumors of childhood. BA triggered an apoptosis pathway different from the one previously identified for standard chemotherapeutic drugs. BA-induced apoptosis was independent of CD95-ligand/receptor interaction and accumulation of wild-type p53 protein, but it critically depended on activation of caspases (interleukin 1beta-converting enzyme/Ced-3-like proteases). FLICE/MACH (caspase-8), considered to be an upstream protease in the caspase cascade, and the downstream caspase CPP32/YAMA/Apopain (caspase-3) were activated, resulting in cleavage of the prototype substrate of caspases PARP. The broad-spectrum peptide inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which blocked cleavage of FLICE and PARP, also completely abrogated BA-triggered apoptosis. Cleavage of caspases was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species. Overexpression of Bcl-2 and Bcl-XL conferred resistance to BA at the level of mitochondrial dysfunction, protease activation, and nuclear fragmentation. This suggested that mitochondrial alterations were involved in BA-induced activation of caspases. Furthermore, Bax and Bcl-xs, two death-promoting proteins of the Bcl-2 family, were up-regulated following BA treatment. Most importantly, neuroblastoma cells resistant to CD95- and doxorubicin-mediated apoptosis were sensitive to treatment with BA, suggesting that BA may bypass some forms of drug resistance. Because BA exhibited significant antitumor activity on patients' derived neuroblastoma cells ex vivo, BA may be a promising new agent for the treatment of neuroectodermal tumors in vivo.
Cancer Res 1997 Nov 01
PMID:Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors. 986 49

The ability of cryptophycin 1, a new potent cytotoxic antimicrotubule agent, to initiate apoptosis was studied. Treatment of cells with cryptophycin 1 (50 pM) rapidly caused morphological changes consistent with the induction of apoptosis. DNA strand breakage and fragmentation of the DNA into oligonucleosome-sized fragments was observed, and this coincided with the loss of cellular DNA. Activation of the cysteine protease CPP32 (caspase 3, YAMA, apopain), a member of the ICE/CED-3-like protease family of apoptosis effectors, was consistent with the execution of cell death by a coordinated sequence of events. Low concentrations of cryptophycin 1 caused mitotic arrest with the formation of abnormal mitotic spindles without affecting interphase microtubule structures. Unlike other microtubule active agents, cryptophycin-induced mitotic arrest persisted for only a brief period before the onset of apoptosis. There was no evidence of release from G2/M cell cycle arrest. Our results show that low concentrations of cryptophycin 1 (50 pM) initiated cell death consistent with apoptosis. These data suggest that the cytotoxic effects of cryptophycin 1 are due in part to its ability to initiate apoptosis rapidly.
Int J Cancer 1997 Nov 04
PMID:Induction of apoptosis by cryptophycin 1, a new antimicrotubule agent. 935 93

Low-dose fractionated gamma-irradiation (three cycles of 5 x 2 Gy) induced cisplatin resistance in HeLa cells. The drug resistance was modest (Rf of about 2) and stable, similar to that found previously in murine cells after irradiation. In the drug-resistant HeLa-C3 cells, flow cytometric analysis revealed a decreased number of apoptotic cells compared with the parental cells. Drug resistance was associated with considerably enhanced expression of the p53 suppressor protein in HeLa-C3 cells after cisplatin exposure but seemed not to be regulated by the bcl-2-dependent pathway. Cisplatin resistance correlated with reduced expression of ICE-related proteases (interleukin-1beta-converting enzyme). Basal levels of the 45-kDa precursor ICE protein were reduced in HeLa-C3 cells, while those of the mature 60-kDa heterotetramer were similar. The CPP32 protease, a member of the ICE family with structural homology but different substrate specificity, was expressed at a lowered level. After drug exposure, there was a slight increase of CPP32 in HeLa-C3 cells, equivalent to about 45% of the level attained in the parental cells. This is in contrast to the CPP32 levels measured after irradiation, which were similar in sensitive and in resistant cells. As the radiosensitivity is unchanged in both cell lines, these results suggest that cisplatin resistance in HeLa-C3 cells is associated with alterations of a CPP32-linked apoptotic pathway, which is affected by the damage caused by cisplatin but not by irradiation. Whether these changes are dependent on the observed p53 modifications is now being studied in resistant clones.
Br J Cancer 1997
PMID:Reduced expression of the ICE-related protease CPP32 is associated with radiation-induced cisplatin resistance in HeLa cells. 937 78

Neuroblastomas frequently show spontaneous regression and differentiation, which may at least partly be regulated by signaling through nerve growth factor and its receptors, TRK-A and p75LNTR. We studied 52 neuroblastic tumors to test whether the cell death-related proteases, interleukin-1 beta converting enzyme (ICE), CPP32, and Ich-1, were involved in the regression of the tumors. High levels of expression of ICE and CPP32 were significantly correlated with a high level of TRK-A expression, single copy of N-myc, younger age, lower stages, and better prognosis. The immunohistochemical studies and Western analyses as well as the terminal dUTP-biotin nick end labeling (TUNEL) method revealed that both ICE and CPP32 were translocated from the cytoplasm into the nuclei in regressing, apoptotic tumor cells. Our results suggest that ICE and CPP32 cysteine proteases may play an important role in regulating the apoptotic process of the favorable neuroblastomas.
Cancer Res 1997 Oct 15
PMID:High levels of expression and nuclear localization of interleukin-1 beta converting enzyme (ICE) and CPP32 in favorable human neuroblastomas. 937 72

The proliferation and survival of a B cell population is necessarily tightly controlled to prevent the arisal of malignancy or autoimmunity. The expansion or elimination of a B cell clone is determined through a complex interaction of the tumour necrosis factor receptor/nerve growth factor receptor family members CD40 and Fas, which are expressed on the B cell surface, with their respective physiological ligands (CD40L and FasL) expressed on the surface of CD4+ T cells. The regulation of B cell growth by signals transduced through CD40 and Fas contributes to the maintenance of peripheral tolerance and likely takes place and in the germinal centres (GC) of secondary lymphoid tissues. In this study, we investigate the relationship between the expression of Fas and B cell survival following engagement of CD40 and Fas in the Epstein-Barr virus-genome-negative Ramos-Burkitt lymphoma (Ramos-BL) B cell line model of GC B lymphocyte selection during maturation of the humoral immune response. We now present evidence that Ramos-BL B cells constitutively express both Fas and FasL on their surface and that expression of Fas, but not FasL, is enhanced following ligation of CD40. Coligation of CD40 and Fas, triggers for growth inhibition, activation of the interleukin-1 beta-converting enzyme, now caspase, family member CPP32 (caspase-3) but not Ich-1L (caspase-2), cleavage of its death substrate poly(ADP-ribose) polymerase, and apoptosis from the G1 phase of cell cycle; engagement of Fas alone fails to trigger for growth inhibition and apoptosis but enhances AgR-mediated cellular death. This CD40-potentiated Fas-triggered growth inhibition and apoptosis occurs in the presence of CD40-induced expression of the anti-apoptotic proteins Bcl-xL and Bcl-2. Taken together, these data indicate that ligation of CD40 facilitates efficient coupling of Fas to the caspase-mediated pathway of apoptosis.
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PMID:Ligation of CD40 potentiates Fas-mediated activation of the cysteine protease CPP32, cleavage of its death substrate PARP, and apoptosis in Ramos-Burkitt lymphoma B cells. 939 1

The goals of this work were to establish a reproducible and effective model of apoptosis in a cell line derived from advanced prostate cancer and to study the role of the caspase family of proteases in mediating apoptosis in this system. The study involved the use of the prostate cancer cell line LNCaP. Apoptosis was induced using the hydroxymethyl glutaryl CoA reductase inhibitor, lovastatin, and was evaluated by agarose gel electrophoresis of genomic DNA, morphological criteria, and terminal deoxynucleotidyl transferase-mediated nick end labeling. Caspases were studied by catalytic activity, mRNA induction, and protein processing. Lovastatin (30 microM) was an effective inducer of apoptosis, causing changes that were evident after 48 h and essentially complete after 96-120 h of treatment. These effects were prevented by the simultaneous addition of mevalonate (300 microM) to the culture medium. Lovastatin induced a proteolytic activity that was able to cleave the enzyme poly(ADP-ribose) polymerase and the substrate Z-DEVD-AFC, which is modeled after the P1-P4 amino acids of the poly(ADP-ribose) polymerase cleavage site. Caspase-7, but not caspase-3, underwent proteolytic activation during lovastatin-induced apoptosis, an effect prevented by mevalonate. Caspase-7 was the only detected interleukin 1beta converting enzyme family protease with DEVD cleavage activity that exhibited lovastatin-induced mRNA up-regulation. Again, mevalonate blocked this effect. Lovastatin-induced apoptosis also was prevented when the caspase inhibitors Z-DEVD-CH2F or Z-VAD-CH2F (100 microM) where added to the medium. These studies have identified lovastatin as a powerful inducer of apoptosis in the cell line LNCaP. Caspase activation was a necessary event for LNCaP cells to undergo apoptosis during treatment with lovastatin. Of the caspases tested, only caspase-7 underwent proteolytic activation after stimulation with lovastatin. Identification of caspase-7 as a potential mediator of lovastatin-induced apoptosis broadens our knowledge of the molecular events associated with programmed cell death in a cell line derived from prostatic epithelium.
Cancer Res 1998 Jan 01
PMID:Caspase-7 is activated during lovastatin-induced apoptosis of the prostate cancer cell line LNCaP. 942 61

The fibroblast culture 180BR, established from a patient showing an adverse response to radiotherapy, has been shown previously to be hypersensitive to ionizing radiation and to be defective in the repair of DNA double-strand breaks. We demonstrate here that the products of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and its regulatory subunits (Ku 70 and Ku 80) are present at normal levels and possess functional activity. The product of the gene mutated in the human genetic disorder ataxia-telangiectasia was also detected in these cells. Apoptosis was detected after high-dose ionizing radiation exposure, and this process was accompanied by specific degradation of DNA-PKcs, ATM, and poly(ADP-ribose) polymerase. Activation of CPP32, an interleukin 1beta converting enzyme-like protease implicated in apoptosis, was also observed in 180BR cells in response to radiation damage. The radiosensitivity observed in 180BR cells can be accounted for, at least in part, by radiation-induced apoptosis, and the defect in these cells is not a gross one in DNA-PKcs or ATM.
Cancer Res 1998 Jan 01
PMID:The radiosensitive cell line 180BR is not defective in the major DNA damage-sensing proteins. 942 62

Apoptosis induced by effector cells of the immune system or by cytotoxic drugs is a main mechanism mediating the prevention or elimination of tumoral cells. For instance, the human T-cell leukemia Jurkat is sensitive to Fas-induced apoptosis and to activation-induced cell death (AICD), and the promonocytic leukemia U937 is sensitive to Fas- and TNF-induced apoptosis. In this work, we have analyzed the mechanisms of resistance to physiological or pharmacological apoptosis in human leukemia by generating highly proliferative (hp) sub-lines derived from Jurkat and U937 cells. These hp sub-lines were resistant to Fas- and TNF-induced apoptosis, as well as to AICD. This was due to the complete loss of Fas and TNFR surface expression and, in the case of Jurkat-derived sub-lines, also of CD3, CD2 and CD59 molecules. The sub-lines also completely lacked the expression of the apoptotic protease CPP32, present in parental cells. Moreover, these sub-lines were no longer sensitive to doxorubicin-induced apoptosis, which was efficiently blocked by the general caspase inhibitor Z-VAD-fmk in the parental cell lines. These data suggest a molecular mechanism for the development of resistance of leukemic cells to physiological and pharmacological apoptosis inducers, giving rise to highly proliferative tumoral phenotypes. These results also indicate that Fas and CPP32 could be useful prognostic markers for the progression and/or therapy outcome of human leukemias.
Int J Cancer 1998 Jan 30
PMID:Resistance to apoptosis correlates with a highly proliferative phenotype and loss of Fas and CPP32 (caspase-3) expression in human leukemia cells. 945 11


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