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

Widespread use of MCF-7 human breast carcinoma cells as a model system for breast cancer has led to variations in these cells between different laboratories. Although several reports have addressed these differences in terms of proliferation and estrogenic response, variations in sensitivity to apoptosis have not yet been described. Tumor necrosis factor alpha (TNF-alpha) has been shown to both induce apoptosis and inhibit proliferation in MCF-7 cells. We observed that TNF-alpha inhibited proliferation in MCF-7 cell variants from three different laboratories (designated M, L, and N). MCF-7 M cells were resistant to TNF-alpha-induced apoptosis, whereas MCF-7 L cells were moderately resistant to the effect of TNF-alpha. A third variant, MCF-7 N, underwent apoptosis when exposed to TNF-alpha. Analysis of the p55 TNF-alpha receptor (TNFR) 1 expression revealed the greatest expression in MCF-7 N cells, whereas the MCF-7 L and M cells expressed 89 and 67% of MCF-7 N cell TNFR1 levels, respectively. Ceramide generation occurred in all three variants in response to TNF-alpha treatment, with MCF-7 N cells expressing the greatest increase. Cleavage of the CPP32/caspase 3 substrate poly(ADP-ribose) was observed in MCF-7 N and L cells as early as 3 and 6 h, respectively, but poly(ADP-ribose) cleavage was not observed in MCF-7 M cells. The delayed protease activation in the L variant may represent the mechanism by which these cells display delayed sensitivity to TNF-a-induced apoptosis. Expression of the Bcl-2, Mcl-1, Bcl-X, Bax, and Bak proteins was analyzed to determine whether the differences in MCF-7 cell sensitivity to apoptosis could be correlated to the differential expression of these proteins. Whereas Bak, Bcl-X, and Mcl-1 levels were identical between variants, the levels of Bcl-2 were 3.5-3.8-fold higher and the levels of Bax were 1.5-1.7-fold lower in the resistant variants (M and L) as compared with those of the sensitive variant (N). Taken together, these results suggest that differences in susceptibility to TNF-alpha-induced apoptosis among MCF-7 breast cancer cell variants may be explained by differences in TNFR expression, ceramide generation, differential expression of the Bcl-2 family of proteins, and protease activation.
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PMID:Differences in susceptibility to tumor necrosis factor alpha-induced apoptosis among MCF-7 breast cancer cell variants. 981 3

Tumor necrosis factor alpha (TNF) or cytotoxic anti-Fas antibodies lead to the activation of apoptotic proteases (caspases) and to sphingomyelinase-mediated ceramide generation. Caspases and ceramide are both known to induce apoptosis on its own, but their relative contribution to Fas- and TNF-induced cell death is not well established. We report here that rapid apoptosis induced by TNF in U937 cells or anti-Fas in Jurkat cells, in the presence of cycloheximide, induced only a very low increase (<20%) in the cell ceramide content. Neither treatment with inhibitors of sphingomyelinases nor incubation of cells with fumonisin B1, which inhibits de novo ceramide synthesis, prevented TNF and Fas-mediated apoptosis. Increasing or depleting the cell ceramide content by prolonged culture in the presence of monensin or fumonisin B1, respectively, did not prevent TNF and Fas-mediated apoptosis. Treatment of cells with sphingomyelinase inhibitors did not affect to the activation of CPP32 (caspase-3) induced by TNF or anti-Fas antibodies. Chromatin condensation and fragmentation in cells treated with anti-Fas or TNF was abrogated by peptide inhibitors of caspases, which also inhibited Fas-, but not TNF-induced cell death. These results indicate that while ceramide does not seem to act as a critical mediator of TNF and Fas-induced apoptosis, it is generated as a consequence of CPP32 activation and could contribute to the spread of the intracellular death signal.
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PMID:Caspases are the main executioners of Fas-mediated apoptosis, irrespective of the ceramide signalling pathway. 1020 Apr 70

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.
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PMID:Activation of NF-kappaB determines the sensitivity of human colon cancer cells to TNFalpha-induced apoptosis. 1078 20

Tumor necrosis factor alpha (TNF-alpha) binding to the TNF receptor (TNFR) initiates apoptosis and simultaneously activates the transcription factor, nuclear factor-kappaB (NF-kappaB), which suppresses apoptosis by an unknown mechanism. Pretreatment with TNF-alpha or interleukin-1beta (IL-1beta), which activated NF-kappaB in the liver, dramatically prevented TNF-alpha-induced liver-cell apoptosis in D-galactosamine (GalN)-sensitized mice, but not anti-Fas antibody-induced hepatotoxicity. This protective effect of TNF-alpha continued for 5 hours after TNF-alpha administration, a time course similar to that found in NF-kappaB activation after TNF-alpha administration. In mice treated with adenoviruses expressing a mutant form of IkappaB, the antiapoptotic effect of TNF-alpha was inhibited in part. Prior TNF-alpha administration was not found to block the activation of caspase-8, although caspase-3 was inhibited in mice treated with TNF-alpha plus GalN/TNF-alpha compared with mice treated with GalN/TNF-alpha. These results indicate that TNFR and Fas independently regulate murine apoptotic liver failure, and that a rapid defense mechanism induced by the activation of NF-kappaB blocks death-signaling at the initiation stage of hepatic apoptosis mediated by TNFR, probably downstream of caspase-8, but not by Fas.
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PMID:Tumor necrosis factor alpha prevents tumor necrosis factor receptor-mediated mouse hepatocyte apoptosis, but not fas-mediated apoptosis: role of nuclear factor-kappaB. 1109 34

Photodynamic therapy (PDT) is a novel cancer treatment utilizing a photosensitizer, visible light and oxygen. PDT with the silicon phthalocyanine Pc 4, a new photosensitizer, is highly effective in cancer cell destruction and tumor ablation. The mechanisms underlying cancer cell killing by PDT are not fully understood. Tumor necrosis factor alpha (TNF) is a multifunctional cytokine that has been implicated in photocytotoxicity. We asked whether recombinant human TNF (rhTNF) affects Pc 4-PDT cytotoxicity in A431 human epidermoid carcinoma cells. Co-treatment of A431 cells with various doses of Pc 4-PDT and a sub-lethal rhTNF dose led to a sub-additive reduction in cell survival. In addition, in the presence of Pc 4-PDT or rhTNF, caspase-3 activity and apoptosis were induced. The combined treatment, however, did not potentiate either caspase-3 activity or apoptosis. Similar to previous findings we observed that Pc 4-PDT initiated a time-dependent extracellular TNF accumulation. The data suggest that: a) PDT and rhTNF induce cancer cell killing through different mechanisms; and b) Pc 4-PDT-induced TNF production is a stress response that may not directly affect photocytotoxicity.
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PMID:Recombinant human tumor necrosis factor alpha does not potentiate cell killing after photodynamic therapy with a silicon phthalocyanine in A431 human epidermoid carcinoma cells. 1117 11

Tumor necrosis factor alpha (TNF-alpha) is a cytokine with multiple roles in the immune system, including the induction and potentiation of cellular functions in neutrophils (PMNs). TNF-alpha also induces apoptotic signals leading to the activation of several caspases, which are involved in different steps of the process of cell death. Inhibition of caspases usually increases cell survival. Here, we found that inhibition of caspases by the general caspase inhibitor zVAD-fmk did not prevent TNF-alpha-induced PMN death. After 6 hours of incubation, TNF-alpha alone caused PMN death with characteristic apoptotic features (typical morphologic changes, DNA laddering, external phosphatidyl serine [PS] exposure in the plasma membrane, Bax clustering and translocation to the mitochondria, and degradation of mitochondria), which coincided with activation of caspase-8 and caspase-3. However, in the presence of TNF-alpha, PMNs died even when caspases were completely inhibited. This type of cell death lacked nuclear features of apoptosis (ie, no DNA laddering but aberrant hyperlobulated nuclei without typical chromatin condensation) and demonstrated no Bax redistribution, but it did show mitochondria clustering and plasma membrane PS exposure. In contrast, Fas-triggered PMN apoptosis was completely blocked by zVAD-fmk. Experiments with scavengers of reactive oxygen species (ROS) and with inhibitors of mitochondrial respiration, with PMN-derived cytoplasts (which lack mitochondria) and with PMNs from patients with chronic granulomatous disease (which have impaired nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) indicated that TNF-alpha/zVAD-fmk-induced cell death depends on mitochondria-derived ROS. Thus, TNF-alpha can induce a "classical," caspase-dependent and a "nonclassical" caspase-independent cell death.
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PMID:Tumor necrosis factor alpha induces a caspase-independent death pathway in human neutrophils. 1239 8

Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that induces apoptosis in a number of cell systems, including osteoblasts. Transforming growth factor beta1 (TGF-beta1) is an abundant growth factor that is known to stimulate bone formation. This study was designed to examine the role of TGF-beta1 on TNF-alpha-induced apoptosis in murine osteoblastic MC3T3-E1 cells. Total RNA was extracted from MC3T3-E1 cells treated with 20 ng/ml of TNF-alpha, 10 ng/ml of TGF-beta1, or combination, for 6 h. TNF-alpha exerted a variety of effects on the apoptotic gene expression in osteoblasts. Ribonuclease protection assays (RPA) revealed that TNF-alpha upregulated the mRNA levels of caspase-1, -7, -11, -12, and FAS. Western blot analysis showed enhanced processing of caspase-1, -7, -11, and -12, with the appearance of their activated enzymes 24 h after TNF-alpha treatment. In addition, caspase-3-like activity was significantly activated following TNF-alpha treatment. Levels of cleaved poly(ADP-ribose) polymerase and FAS protein were also elevated by TNF-alpha. Finally, Hoechst staining, terminal deoxynucleotidyl-transferase nick-end labeling (TUNEL) assay, and oligonucleosome ELISA all indicated that TNF-alpha induced apoptosis. In contrast, the addition of TGF-beta1 attenuated all of the aforementioned effects of TNF-alpha. Our results demonstrate that TGF-beta1 can decrease TNF-alpha-induced apoptosis in murine osteoblasts at least in part by attenuating TNF-alpha-induced caspase gene expression.
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PMID:TGF-beta1 inhibits multiple caspases induced by TNF-alpha in murine osteoblastic MC3T3-E1 cells. 1243 78

The ability of keratinocyte growth factor 1 to modulate apoptosis in the absence of proliferation was studied in vitro. A HaCaT scrape wound model was developed in which dense monolayers prior to wounding were cultured to quiescence in defined media with hydroxyurea at concentrations that blocked proliferation without loss of cell viability. Scrape wounding was then found to induce apoptosis, originating at the wound edge, but subsequently radiating away over a 24 h period to encompass areas not originally damaged. Keratinocyte growth factor 1 inhibited this radial progression of apoptosis in a concentration-dependent manner up to 20 ng per mL with induced migration present at the wound edge. The extent of this rescue was modulated by the concentration of Ca2+ prior to wounding. In control wound cultures apoptotic bodies were found in cells adjacent to the wound interface but were greatly reduced in keratinocyte-growth-factor-1-treated groups. Keratinocyte growth factor 1 receptor expression was significantly induced within two to three cell widths of the scraped wound edge, at levels far exceeding those found at the leading edge of a nonwounded epithelial sheet. Tumor necrosis factor alpha (1-5 ng per mL) or Escherichia coli lipopolysaccharide (10-50 ng per mL) exacerbated scrape-induced early apoptosis (1-4 h), but was largely ameliorated by coculture with keratinocyte growth factor 1. Keratinocyte growth factor 1 protection was associated with a reduction in both caspase-3 activation and cytokeratin-19 loss. Protected wound edges were also associated with the maintenance of e-cadherin expression and induction of beta1 integrin and actin stress fiber organization. These results suggest that keratinocyte growth factor 1 may play a role in limiting mechanically induced apoptotic processes at the epithelial wound edge in a manner that is distinct from its proliferative function.
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PMID:Keratinocyte growth factor 1 inhibits wound edge epithelial cell apoptosis in vitro. 1496 12

Tumor necrosis factor alpha (TNFalpha) is an immunomodulatory and proinflammatory cytokine implicated in neuroinflammation and neuronal damage in response to cerebral ischemia. Tumor necrosis factor-alpha converting enzyme (TACE or ADAM17) is a key sheddase that releases TNFalpha from its inactive cell-bound precursor. Using a selective small molecule inhibitor of TACE, DPH-067517, we tested the hypothesis that inhibition of TNFalpha formation might have a salutary effect in ischemic stroke induced by embolic occlusion of the middle cerebral artery (MCAO). DPH-067517 selectively inhibited TACE enzyme activity in vitro (K(i) = 2.8 nM), and effectively suppressed ischemia-induced increase in soluble TNFalpha in brain tissue after systemic administration. DPH-067517 (3 and 30 mg/kg, i.p. administered 15 min before MCAO) produced 43% (n = 8, p = 0.16) and 58% (n = 8, p < 0.05) reduction in infarct size and 36% (p < 0.05) and 23% (p < 0.05) reduction in neurological deficits, respectively. The salutary effect of DPH-067517 in ischemic brain injury was also observed when the first dose was administrated 60 min after the onset of ischemia. Inhibition of TACE had no effect on apoptosis measured by levels of active caspase-3 expression and DNA fragmentation. Our data suggest that inhibition of TACE might be a potential therapeutic strategy for neuroprotection after focal ischemic stroke.
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PMID:Inhibition of tumor necrosis factor-alpha-converting enzyme by a selective antagonist protects brain from focal ischemic injury in rats. 1504 18

Tumor necrosis factor alpha (TNFalpha) can trigger both cell survival and apoptosis. In the present study, from the flow cytometry results, we found that the prolonged-treatment of TNFalpha until 24 h, resulted apoptosis in AM-1 cells (ameloblastoma cell line). These results were confirmed by DAPI staining, which showed nuclear fragmentation feature of AM-1 cells under treatment of TNFalpha. Our further investigation using specific caspase inhibitors showed that caspase-3 played a crucial role in mediating TNFalpha-induced apoptosis in AM-1 cells. In addition, significant elevation of TNFalpha potential in inducing apoptosis was seen by applying LY294002, phosphatidylinositol-3-OH kinase (PI3K) inhibitor, or U0126, mitogen-activated extracellular-regulated kinase (MEK1/2) inhibitor, prior to the treatment of TNFalpha in AM-1 cells. These results suggested that TNFalpha induced both cell survival and apoptosis pathways in ameloblastoma and potential of TNFalpha in inducing apoptosis can be improved by inhibiting TNFalpha-induced Akt and p44/42 mitogen-activated protein kinase (MAPK) cell survival pathways.
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PMID:Inhibition of Akt and MAPK pathways elevated potential of TNFalpha in inducing apoptosis in ameloblastoma. 1614 May 62


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