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

Proteases belonging to the caspase family play a crucial role in apoptotic processes. Identification of protein cleavage specific to apoptosis may therefore provide further information about the mechanisms of apoptosis. In this study, apoptosis and necrosis were induced in cells of the human colon cancer cell lines, WiDr and DLD-1, and the resulting protein cleavage patterns investigated for beta-catenin. beta-Catenin was detected as a 92 kDa protein in control viable cells, while 65-72 kDa beta-catenin cleavage fragments were characteristically observed in apoptotic cells. These fragments were not observed in necrotic cell death. Similar apoptosis-specific beta-catenin cleavage was also demonstrated in the rat hepatoma cell line McA-RH7777, suggesting that the beta-catenin cleavage is a common event in apoptosis in various cell types. The formation of 65-72 kDa beta-catenin cleavage fragments was completely prevented by a caspase-1 inhibitor Z-VAD-CH2F and a caspase-3 inhibitor Z-DEVD-CH2F, indicating that the cleavage is associated with caspase-dependent process. Since beta-catenin is implicated in cell adhesion and signal transduction, these findings may suggest various possible roles of beta-catenin degradation in the dramatic cytoskeletal and morphological changes, as well as signaling events that accompany apoptosis.
 ...
PMID:Apoptosis-associated cleavage of beta-catenin in human colon cancer and rat hepatoma cells. 1022 75

At present, cancer therapy of solid tumors, such as lung and colorectal cancer, is unsatisfactory. Recently, oxygenated sterols have shown selective cytotoxicity against tumor cells. In this study, the cytotoxicity of 7 beta-hydroxycholesterol (7 beta HC) and two water-soluble derivatives of 7 beta HC, i.e. 7 beta HC-bis-hemisuccinate [disodium salt] (7 beta HC-HS) and 7 beta HC-bis-hemisuccinate-diethanolaminoate (7 beta HC-EA), was determined in DLD-1, KM20L2, HCT-116, HT-29 and SW620 colon carcinoma cell lines using a cell count assay. IC50 values of the two water-soluble derivatives were, on the whole, comparable to 7 beta HC lying in the range of 3-10 microM. In addition, the water-soluble derivatives were able to induce apoptosis in the examined DLD-1 and KM20L2 colon carcinoma cell lines in contrast to the parent compound 7 beta HC, as shown by DNA fragmentation, by the cleavage of DNA repair enzyme poly(ADP) ribose polymerase (PARP), and by the proteolytic cleavage of caspase-3 (CPP32). Due to the improved water-solubility of 7 beta HC-HS and 7 beta HC-EA and their promising antitumor activity in vitro, animal studies in suitable tumor models are warranted.
 ...
PMID:Antitumor activity and induction of apoptosis by water-soluble derivatives of 7 beta-hydroxycholesterol in human colon carcinoma cell lines. 1062 83

Tumor necrosis factor alpha (TNFalpha) generates a potent cytotoxic effect, however many cancer cells are resistant to TNFalpha-mediated killing and the cause of the differential sensitivity remains to be elucidated. In this study, we demonstrated that TNFalpha induced cell death in four different human colon cancer cell lines. The degree of cytotoxic effect was different in each cell line, in that HCT-15 was relatively sensitive, while DLD-1, HT-29 and WiDr were relatively resistant. TNFalpha induced apoptotic changes such as morphological changes, DNA fragmentation and activation of caspase-3 in HCT-15, but to a lesser degree in the others. Transcriptional expression of TNFR1(p55), as well as that of FLICE, Fas, FADD, DR3, FAF, TRADD, and RIP was similar in these cell lines, indicating that the susceptibility to TNFalpha-induced apoptosis may not be determined by the constitutive expression level of these factors. Interestingly, the cytotoxic effect of TNFalpha was well correlated with the DNA binding activity of NF-kappaB in the colon cancer cell lines. Further, the overexpression of a non-phosphorylated mutant form of IkappaBalpha enhanced the cytotoxicity of TNFalpha in the resistant cell line, DLD-1, indicating that NF-kappaB activity may determine the sensitivity of colon cancer cells to TNFalpha-induced apoptosis. Thus, our results indicate that modulation of NF-kappaB activity may provide a useful tool to sensitize colon cancer cells to TNFalpha treatment.
 ...
PMID:Activation of NF-kappaB determines the sensitivity of human colon cancer cells to TNFalpha-induced apoptosis. 1078 20

Cancer cells express different levels of apoptosis-promoting Bax protein. The present study evaluated whether induction of Bax initiates apoptosis and whether Bax overexpression enhances apoptosis induced by several chemotherapeutic agents in DLD-1 colon cancer cells, which originally express a high level of endogenous Bax protein and a low level of Bcl-2 protein. To investigate these two points, parental DLD-1 cells were transfected with the Tet-On Bax induction system (pTet-On and pTRE-Bax plasmids), and stable transduced cells were obtained. Induction of Bax by the Tet-On system initiated cytochrome c release from mitochondria, caspase-3 activation, and apoptosis to some extent in DLD-1 cells. Apoptosis induced by a chemotherapeutic agent, 5-fluorouracil, mitomycin C, paclitaxel, doxorubicin, or cisplatin, was enhanced by Bax overexpression. These findings suggest that Bax-overexpression-based gene therapy combined with chemotherapy would be effective in the treatment of colon cancer.
 ...
PMID:Bax induction activates apoptotic cascade via mitochondrial cytochrome c release and Bax overexpression enhances apoptosis induced by chemotherapeutic agents in DLD-1 colon cancer cells. 1112 25

One of the main functions of the tumor suppressor p53 is the induction of programmed cell death. Here we investigated in detail the molecular mechanisms that underlay p53 transactivation-dependent apoptosis in the human colon cancer cell line DLD-1. Although p53 upregulated the death receptors Fas, TRAIL-R1 and TRAIL-R2 in this cell line, p53-induced cell death occurred without detectable caspase-8 activation whereas, activation of caspase-9 and caspase-3 was readily observed. In addition to the upregulation of death receptors, p53 induced the pro-apoptotic Bcl-2 family members Bik and Bak and downregulated the anti-apoptotic Bcl-xL protein. Moreover, in RNase protection assay analyses as well as in reporter gene analyses we found a p53-dependent upregulation of the death receptor-inhibitory protein cFLIP. Together, these data argue for a p53-mediated activation of the mitochondrial pathway of apoptosis. In contrast to recently published data obtained in different cellular systems, there was no evidence for an essential role of NF-kappaB in p53-induced cell death. Moreover, induction of p53 interfered with TNF-induced NF-kappaB activation independently from apoptosis-induction.
 ...
PMID:p53 upregulates cFLIP, inhibits transcription of NF-kappaB-regulated genes and induces caspase-8-independent cell death in DLD-1 cells. 1131 89

Galectin-7 is normally expressed in all types of stratified epithelia, but is significantly down-regulated in squamous cell carcinomas. This protein was recently found to be highly inducible by p53 in a colon carcinoma cell line, DLD-1, and designated as PIG1 (for p53-induced gene 1). We studied transfectants of HeLa and DLD-1 cells ectopically expressing this protein and found that they were more susceptible to apoptosis than control transfectants. This was observed in apoptosis induced by mechanistically distinct stimuli, suggesting that galectin-7 acts on a common point in the apoptosis signaling pathways. Further analyses of actinomycin D-induced apoptosis demonstrated that galectin-7 expression causes enhanced caspase-3 activity and poly(ADP-ribose) polymerase cleavage, and the potentiation of apoptosis by galectin-7 was completely abrogated by a caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone. In addition, galectin-7 transfectants displayed accelerated mitochondrial cytochrome c release and up-regulated JNK activity upon apoptosis induction. Several lines of evidence indicate that the effect on apoptosis is not due to the lectin functioning extracellularly through interactions with cell surface glycoconjugates. In fact, this lectin is found to localize in nuclei and cytoplasm of the transfectants and the transformed keratinocyte line HaCaT. Therefore, galectin-7 is a pro-apoptotic protein that functions intracellularly upstream of JNK activation and cytochrome c release. DNA microarray analysis revealed genes that are differentially expressed between galectin-7 and control transfectants. Some of them are potentially contributory to this lectin's proapoptotic function and these include redox-related genes monoamine oxidase B, ryanodine receptor 2, and glutathione S-transferase Mu 3.
 ...
PMID:Galectin-7 (PIG1) exhibits pro-apoptotic function through JNK activation and mitochondrial cytochrome c release. 1170 6

In a search for new anticancer agents, we identified that 2[[3-(2,3-dichlorophenoxy) propyl]amino]ethanol (2,3-DCPE) induced apoptosis more effectively in various cancer cells than in normal human fibroblasts. We further evaluated the cell-killing effects of this compound in vitro in several human cancer cell lines and normal human fibroblasts. A cell viability assay showed that IC(50)s for human colon cancer cell lines LoVo and DLD-1, for human lung cancer cell lines H1299 and A549, and for normal human fibroblasts were 0.89, 1.95, 2.24, 2.69, and 12.6 micro M, respectively. Subsequent studies revealed that 2,3-DCPE could cause cleavage of caspase-8, caspase-3, caspase-9, and poly(ADP-ribose) polymerase and release of cytochrome c in cancer cells but not in normal human fibroblasts. Our data also showed that 2,3-DCPE attenuated the protein level of Bcl-XL and that apoptosis induction by 2,3-DCPE could be blocked by enforced overexpression of Bcl-XL. Our results suggest that 2,3-DCPE might be a potential new anticancer agent.
 ...
PMID:Induction of apoptosis and down-regulation of Bcl-XL in cancer cells by a novel small molecule, 2[[3-(2,3-dichlorophenoxy)propyl]amino]ethanol. 1487 45

The protease inhibitor ritonavir is an integral part of current antiretroviral therapy targeting human immunodeficiency virus. Recent studies demonstrate that ritonavir induces apoptotic cell death with high efficiency in lymphoblastoid cell lines. Moreover, ritonavir can suppress activation of the transcription factor nuclear factor-kappaB and is an inhibitor of interleukin-1beta and tumor necrosis factor-alpha production in peripheral blood mononuclear cells. Thus, ritonavir appears to have anti-inflammatory properties. In the present study, we investigated in DLD-1 colon carcinoma cell effects of ritonavir on apoptotic cell death and expression of heme oxygenase-1 (HO-1), an anti-inflammatory enzyme that may be critically involved in the modulation of colonic inflammation. Compared to unstimulated control, ritonavir resulted in a moderate increase in the rate of apoptotic cell death as observed after 20 h of incubation. Notably, ritonavir potently synergized with the short-chain fatty acid butyrate for induction of caspase-3-dependent apoptosis in DLD-1 cells. Ritonavir enhanced mRNA and protein expression of HO-1 in DLD-1 cells. Ritonavir-induced HO-1 protein was suppressed by SB203580 or SB202190 and preceded by immediate upregulation of cellular c-Fos and c-Jun protein levels. This process was associated with induction of activator protein-1 as detected by electrophoretic mobility shift analysis. The present data suggest that ritonavir has the potential to curb colon carcinogenesis by reducing cell growth via mechanisms that include apoptosis and by simultaneously modulating colonic inflammation via induction of anti-inflammatory HO-1.
 ...
PMID:The HIV protease inhibitor ritonavir synergizes with butyrate for induction of apoptotic cell death and mediates expression of heme oxygenase-1 in DLD-1 colon carcinoma cells. 1550 50

The flavanone naringenin (Nar), especially abundant in the Mediterranean diet, is reported to have anti-proliferative effects in many cancer cell lines. Antioxidant activities, kinase and glucose uptake inhibition have been proposed as molecular mechanisms for these effects. In addition, an anti-estrogenic activity has been observed but, at the present, it is poorly understood whether this latter activity could play a role in the Nar anti-tumoral effects. Here, we tested the ability of Nar to activate a specific, rapid signal transduction pathway committed to the generation of an apoptotic cascade in the presence of one of the two estrogen receptor (ER) isoforms (i.e., ERalpha or ERbeta). Cancer cells containing transfected (human cervix epitheloid carcinoma HeLa cells) or endogenous ERalpha (human hepatoma HepG2 cells) or ERbeta (human colon adenocarcinoma DLD-1 cells) were used. Our results show that Nar exerts an anti-proliferative effect only in the presence of ERalpha or ERbeta. Moreover, Nar stimulation induces the activation of p38/MAPK leading to the pro-apoptotic caspase-3 activation and to the poly(ADP-ribose) polymerase cleavage in all cancer cell lines considered. Notably, Nar shows an anti-estrogenic effect only in ERalpha containing cells; whereas in ERbeta containing cells, Nar mimics the 17beta-estradiol effects. These findings indicate new steps in the mechanism underlying ER-dependent anti-proliferative effects of Nar suggesting new potential chemopreventive actions of flavonoids on cancer growth.
 ...
PMID:Mechanisms of naringenin-induced apoptotic cascade in cancer cells: involvement of estrogen receptor alpha and beta signalling. 1554 29

Sea cucumber is a health-beneficial food, and contains a variety of physiologically active substances including glycosphingolipids. We show here the sphingoid base composition of cerebrosides prepared from sea cucumber and the cytotoxicity against human colon cancer cell lines. The composition of sphingoid bases prepared from sea cucumber was different from that of mammals, and the major constituents estimated from mass spectra had a branched C17-19 alkyl chain with 1-3 double bonds. The viability of DLD-1, WiDr and Caco-2 cells treated with sea cucumber sphingoid bases was reduced in a dose-dependent manner and was similar to that of cells treated with sphingosine. The sphingoid bases induced such a morphological change as condensed chromatin fragments and increased the caspase-3 activity, indicating that the sphingoid bases reduced the cell viability by causing apoptosis in these cells. Sphingolipids of sea cucumber might therefore serve as bioactive dietary components to suppress colon cancer.
 ...
PMID:Isolation of sphingoid bases of sea cucumber cerebrosides and their cytotoxicity against human colon cancer cells. 1715 82


1 2 3 4 5 Next >>