Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A pharmacological dose (2.5-10 microM) of 17alpha-estradiol (17alpha-E(2)) exerted a cytotoxic effect on human leukemias Jurkat T and U937 cells, which was not suppressed by the estrogen receptor (ER) antagonist ICI 182,780. Along with cytotoxicity in Jurkat T cells, several apoptotic events including mitochondrial cytochrome c release, activation of caspase-9, -3, and -8, PARP degradation, and DNA fragmentation were induced. The cytotoxicity of 17alpha-E(2) was not blocked by the anti-Fas neutralizing antibody ZB-4. While undergoing apoptosis, there was a remarkable accumulation of G(2)/M cells with the upregulatoin of cdc2 kinase activity, which was reflected in the Thr56 phosphorylation of Bcl-2. Dephosphorylation at Tyr15 and phosphorylation at Thr161 of cdc2, and significant increase in the cyclin B1 level were underlying factors for the cdc2 kinase activation. Whereas the 17alpha-E(2)-induced apoptosis was completely abrogated by overexpression of Bcl-2 or by pretreatment with the pan-caspase inhibitor z-VAD-fmk, the accumulation of G(2)/M cells significantly increased. The caspase-8 inhibitor z-IETD-fmk failed to influence 17alpha-E(2)-mediated caspase-9 activation, but it markedly reduced caspase-3 activation and PARP degradation with the suppression of apoptosis, indicating the contribution of caspase-8; not as an upstream event of the mitochondrial cytochrome c release, but to caspase-3 activation. In the presence of hydroxyurea, which blocked the cell cycle progression at the G(1)/S boundary, 17alpha-E(2) failed to induce the G(2)/M arrest as well as apoptosis. These results demonstrate that the cytotoxicity of 17alpha-E(2) toward Jurkat T cells is attributable to apoptosis mainly induced in G(2)/M-arrested cells, in an ER-independent manner, via a mitochondria-dependent caspase pathway regulated by Bcl-2.
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PMID:17Alpha-estradiol arrests cell cycle progression at G2/M and induces apoptotic cell death in human acute leukemia Jurkat T cells. 1860 76

Overriding the G(2) DNA damage checkpoint permits precocious entry into mitosis that ultimately leads to mitotic catastrophe. Mitotic catastrophe is manifested by an unscheduled activation of CDK1, caspase activation and apoptotic cell death. We found that although cyclin B1 was required for mitotic catastrophe, it was cleaved into a approximately 35 kDa protein by a caspase-dependent mechanism during the process. Cyclin B1 cleavage occurred after Asp123 in the motif ILVD(123) downward arrow, and mutation of this motif attenuated the cleavage. Cleavage was abolished by a pan-caspase inhibitor as well as by specific inhibitors for the effector caspase-6 and the initiator caspase-8. Cleavage created a truncated cyclin B1 lacking part of the NH(2)-terminal regulatory domain that included the destruction box sequence. Although cleavage of cyclin B1 itself was not absolutely required for mitotic catastrophe, expression of the truncated product enhanced cell death. In support of this, ectopic expression of this truncated cyclin B1 was not only sufficient to induce mitotic block and apoptosis but also enhanced mitotic catastrophe induced by ionizing radiation and caffeine. These data underscore a possible linkage between mitotic and apoptotic functions by caspase-dependent processing of mitotic activators.
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PMID:Generation of an indestructible cyclin B1 by caspase-6-dependent cleavage during mitotic catastrophe. 1882 Jul 6

Osteosarcoma is highly resistant to current chemotherapy regimens. Novel therapeutic approaches, potentially involving targeting of specific survival pathways, are needed. We used 17-AAG to inhibit Hsp90 and rapamycin to inhibit mTOR, in the osteosarcoma cell lines, HOS and KHOS/NP. HOS and KHOS cells were treated for 24 and 48 h with 17-AAG or rapamycin and studied drug-induced apoptosis, cell cycle, mitochondrial membrane potential and levels of reduced glutathione (GSH), dephosphorylation of signal transduction proteins in the Akt/MAP kinase pathway and mTOR signaling. 17-AAG was a potent inducer of apoptosis, involving effective depletion of GSH and mitochondrial membrane (MM) depolarization, strong activation of caspase-8 and -9 and release of AIF from mitochondria to the cytosol. Furthermore, 17-AAG down-regulated pAkt, p44Erk, p-mTOR, p70S6, TSC1/2 and pGSK-3beta. Treatment with 17-AAG also caused down-regulation of cyclin D1, GADD45a, GADD34 and pCdc2 and upregulation of cyclin B1 and mitotic block. A decrease in Hsp90 and increase in Hsp70 and Hsp70 C-terminal fragments were also observed. Rapamycin was a less potent inducer of apoptosis, involving a small decrease in GSH and MM potential with no activation of caspases or release of AIF. Rapamycin strongly inhibited cell growth with an increase in G1 and a decrease in S-phase of the cell cycle concomitant with down-regulation of cyclin D1. Rapamycin also down-regulated the activity of p70S6, pAkt and p-mTOR, but had no effect on pGSK-3beta, p44Erk, pCdc2, TSC1/2 or Hsp70 or Hsp90. We conclude that Hsp90 inhibition merits further study in the therapy of osteosarcoma.
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PMID:Targeted therapy of human osteosarcoma with 17AAG or rapamycin: characterization of induced apoptosis and inhibition of mTOR and Akt/MAPK/Wnt pathways. 1914 92

Shi-Liu-Wei-Liu-Qi-Yin (SLWLQY) was traditionally used to treat cancers. However, scientific evidence of the anticancer effects still remains undefined. In this study, we aimed to clarify the possible mechanisms of SLWLQY in treating cancer. We evaluated the effects of SLWLQY on apoptosis-related experiments inducing in TSGH-8301 cells by (i) 3-(4,5-dimethylthiazol-zyl)-2,5-diphenylterazolium bromide (MTT) for cytotoxicity; (ii) cell-cycle analysis and (iii) western blot analysis of the G2/M-phase and apoptosis regulatory proteins. Human bladder carcinoma TSGH-8301 cells were transplanted into BALB/c nude mice as a tumor model for evaluating the antitumor effect of SLWLQY. Treatment of SLWLQY resulted in the G2/M phase arrest and apoptotic death in a dose-dependent manner, accompanied by a decrease in cyclin-dependent kinases (cdc2) and cyclins (cyclin B1). SLWLQY stimulated increases in the protein expression of Fas and FasL, and induced the cleavage of caspase-3, caspase-9 and caspase-8. The ratio of Bax/Bcl(2) was increased by SLWLQY treatment. SLWLQY markedly reduced tumor size in TSGH-8301 cells-xenografted tumor tissues. In the tissue specimen, SLWLQY up-regulated the expression of Fas, FasL and Bax proteins, and down-regulated Bcl(2) as well as in in vitro assay. Our results showed that SLWLQY reduced tumor growth, caused cell-cycle arrest and apoptosis in TSGH-8301 cells via the Fas and mitochondrial pathway.
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PMID:Aqueous Extract of Shi-Liu-Wei-Liu-Qi-Yin Induces G2/M Phase Arrest and Apoptosis in Human Bladder Carcinoma Cells via Fas and Mitochondrial Pathway. 1938 39

Our previous studies have demonstrated that nuclear factor I-C (NFI-C) null mice developed short molar roots that contain aberrant odontoblasts and abnormal dentin formation. Based on these findings, we performed studies to elucidate the function of NFI-C in odontoblasts. Initial studies demonstrated that aberrant odontoblasts become dissociated and trapped in an osteodentin-like mineralized tissue. Abnormal odontoblasts exhibit strong bone sialoprotein expression but a decreased level of dentin sialophosphoprotein expression when compared with wild type odontoblasts. Loss of Nfic results in an increase in p-Smad2/3 expression in aberrant odontoblasts and pulp cells in the subodontoblastic layer in vivo and primary pulp cells from Nfic-deficient mice in vitro. Cell proliferation analysis of both cervical loop and ectomesenchymal cells of the Nfic-deficient mice revealed significantly decreased proliferative activity compared with wild type mice. In addition, Nfic-deficient primary pulp cells showed increased expression of p21 and p16 but decreased expression of cyclin D1 and cyclin B1, strongly suggesting cell growth arrest caused by a lack of Nfic activity. Analysis of the pulp and abnormal dentin in Nfic-deficient mice revealed an increase in apoptotic activity. Further, Nfic-deficient primary pulp cells exhibited an increase in caspase-8 and -3 activation, whereas the cleaved form of Bid was hardly detected. These results indicate that the loss of Nfic leads to the suppression of odontogenic cell proliferation and differentiation and induces apoptosis of aberrant odontoblasts during root formation, thereby contributing to the formation of short roots.
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PMID:Nuclear factor I-C is essential for odontogenic cell proliferation and odontoblast differentiation during tooth root development. 1938 89

New chemotherapeutic strategy should be investigated to enhance clinical management in salivary gland adenoid cystic carcinoma (ACC). Recently, sulforaphane (SFN), as a natural compound from cruciferous vegetables exhibits a potent anti-cancer activity in various tumor cells, but remains uncertain in ACC cells. The present study examined whether SFN suppresses proliferation and in ACC cells, if so, the possible molecular targets would be further investigated. Cell survives, apoptosis, cell cycle progression and molecular targets were identified by multiple detecting techniques, including trypan blue dye exclusion assay, electron microscopy, AO/EB staining, flow cytometry and immunoblotting in human lung high metastasis cell line of salivary gland adenoid cystic carcinoma (ACC-M). The results showed that 5-20 microM SFN suppressed proliferation and induced apoptosis of ACC-M cells in dose- and time-dependent manners. Cell cycle analysis demonstrated treatment of ACC-M cells with 20 microM SFN resulted in G(2)/M cell cycle arrest, which was associated with a marked decline in protein levels of G(2)/M regulatory proteins including cyclin B1 and cyclin-dependent kinase 1 (Cdk1). In terms of apoptosis, SFN increased the expression of Bax and decreased the level of Bcl-2 and subsequently triggered release of cytochrome c from mitochondria and activation of caspase-3, but Fas level and caspase-8 activity remained unchanged at all time points. Furthermore, levels of nuclear factor-kappaB (NF-kappaB) p65 in both of the cytoplasm and the nucleus have also been markedly suppressed by SFN in a time-dependent manner. Taken together, these results suggest SFN inhibits cell growth via inducing G(2)/M cell arrest and apoptosis in ACC-M cells. These events have been associated with SFN-regulated multiple targets involved in ACC-M cell proliferation. The present study provides an evidence for testing SFN efficacy in vivo and warranting future investigations to exam the clinical potential of SFN in ACC chemotherapy.
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PMID:Sulforaphane induces G2-M arrest and apoptosis in high metastasis cell line of salivary gland adenoid cystic carcinoma. 1958 18

Liverwort constituents have been reported to exert a broad spectrum of biological activities. In this study, we used a bioactivity-guided separation of an extract from the liverwort species Marchantia emarginata subsp. tosana to determine its anticancer activity. A high level of the active ingredient was isolated from this liverwort and its chemical structure was identified and characterized by various spectra. It was found to be identical to a well-known compound, marchantin A, a cyclic bisbibenzyl ether. However, no anticancer activities of this compound have previously been reported. We found that marchantin A efficiently induced cell growth inhibition in human MCF-7 breast cancer cells, with an IC(50) of 4.0microg/mL. Fluorescence microscopy and a Western blot analysis indicated that marchantin A actively induced apoptosis of MCF-7 cells. The levels of cleaved caspase-8, cleaved caspase-3, cleaved caspase-9, and cleaved poly (ADP ribose) polymerase (PARP) increased. However, the level of Bid markedly decreased in a dose- and time-dependent manner. We also evaluated the anticancer activities of marchantin A on the regulation of cell cycle regulators such as p21, p27, cyclin B1, and cyclin D1. The p21 and p27 gene expressions increased markedly while cyclin B1 and D1 gene expression decreased markedly by treatment with marchantin A. Many report demonstrated that liverwort was suggested to possess potent antioxidant activity. Our results indicate that marchantin A possesses free radical-scavenging activity (EC(50)=20microg/mL). Taken together, for the first time, the compound marchantin A from liverworts demonstrated to be a potent inducer of apoptosis in MCF-7 cells.
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PMID:Marchantin A, a cyclic bis(bibenzyl ether), isolated from the liverwort Marchantia emarginata subsp. tosana induces apoptosis in human MCF-7 breast cancer cells. 1991 53

Aloe-emodin (AE), a natural, biologically active compound from the rhizome of Rheum palmatum, has been shown to induce apoptosis in several cancer cell lines in vitro. However, its molecular mechanism of action in the apoptosis induction of human nasopharyngeal carcinoma (NPC) cells has not been explored. This study shows that AE induced G(2)/M phase arrest by increasing levels of cyclin B1 bound to Cdc2, and also caused an increase in apoptosis of NPC cells, which was characterized by morphological changes, nuclear condensation, DNA fragmentation, caspase-3 activation, cleavage of poly (ADP-ribose) polymerase (PARP) and increased sub-G(1) population. Treatment of NPC cells with AE also resulted in a decrease in Bcl-X(L) and an increase in Bax expression. Ectopic expression of Bcl-X(L) but not Bcl-2 or small interfering RNA (siRNA)-mediated attenuation of Bax suppressed AE-induced apoptotic cell death. AE-induced loss of mitochondrial membrane potential (MMP) and increase in cellular Ca(++) content, reactive oxygen species (ROS) and apoptotic cell death were suppressed by the treatment of cyclosporin A (CsA) or caspase-8 inhibitor Z-IETD-FMK. Co-treatment with caspase-9 inhibitor Z-LEHD-FMK could inhibit AE-induced cell death and the activation of caspase-3 and -9. In addition, suppression of caspase-8 with the specific inhibitor Z-IETD-FMK inhibited AE-induced the activation of Bax, the cleavage of Bid, the translocation of tBid to the mitochondria and the release of cytochrome c, apoptosis-inducing factor (AIF) and Endo G from the mitochondria and subsequent apoptosis. Taken together, these results indicate that the caspase-8-mediated activation of the mitochondrial death pathway plays a critical role in AE-induced apoptosis of NPC cells.
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PMID:Aloe-emodin induces apoptosis of human nasopharyngeal carcinoma cells via caspase-8-mediated activation of the mitochondrial death pathway. 1994 42

The incidence of thyroid cancer increases with age, and it is twice in women as common as in men. The undifferentiated thyroid cancer (UTC) is the most aggressive of all thyroid cancers. Unfortunately, there are almost no efficacious therapeutic modalities. It is important to develop some new effective therapies. Evodiamine is a chemical extracted from a kind of Chinese herb named Wu-Chu-Yu and has been demonstrated to be effective in preventing the growth of a variety of cancer cells. In the present study, the mechanism by which evodiamine inhibited the undifferentiated thyroid cancer cell line ARO was examined. Based on 3-(4,5-dimethylthiazol -2-yle)2,5-diphenyltetrazolium bromide (MTT) assay, cell proliferation rate was reduced dose-dependently by evodiamine, but not by rutaecarpine. According to the flow cytometric analysis, evodiamine treatment resulted in G2/M arrest and DNA fragmentation in ARO cells. The G2/M arrest was accompanied with an increase of the expression of cdc25C, cyclin B1, and cdc2-p161 protein, and it was also with a decrease of the expression of cdc2-p15. Furthermore, by using the TUNEL assay, evodiamine-induced apoptosis was observed at 48 h and extended to 72 h. Western blotting demonstrated that evodiamine treatment induced the activation of caspase-8, caspase-9, caspase-3, and the cleavage of poly ADP-ribose polymerase (PARP). These results suggested that evodiamine inhibited the growth of the ARO cells, arrested them at M phase, and induced apoptosis through caspases signaling.
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PMID:Anti-proliferative effects of evodiamine on human thyroid cancer cell line ARO. 2050 48

Caspase activation is a hallmark of apoptosis. However, the molecular mechanisms underlying the regulation of caspase-8 activation within the extrinsic death pathway are not well understood. In this study, we demonstrate that procaspase-8 is phosphorylated in mitotic cells by Cdk1/cyclin B1 on Ser-387, which is located at the N terminus of the catalytic subunit p10. This phosphorylation of procaspase-8 on Ser-387 occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes. Furthermore, RNA interference-mediated silencing of cyclin B1 or treatment with the Cdk1 inhibitor RO-3306 enhances the Fas-mediated activation and processing of procaspase-8 in mitotic cells. A nonphosphorylatable procaspase-8 (S387A) facilitates Fas-induced apoptosis during mitosis. Our findings suggest that Cdk1/cyclin B1 activity shields human cells against extrinsic death stimuli and unravel the molecular details of the cross talk between cell cycle and extrinsic apoptotic pathways. Finally, this new mechanism may also contribute to tumorigenesis.
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PMID:Cdk1/cyclin B1 controls Fas-mediated apoptosis by regulating caspase-8 activity. 2093 73


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