Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Death receptor signaling is initiated by the assembly of the death-inducing signaling complex, which culminates in the activation of the initiator caspase, either caspase-8 or caspase-10. A family of viral and cellular proteins, known as FLIP, plays an essential role in the regulation of death receptor signaling. Viral FLIP (v-FLIP) and short cellular FLIP (c-FLIPS) inhibit apoptosis by interfering with death receptor signaling. The structure and mechanisms of v-FLIP and c-FLIPS remain largely unknown. Here we report a high resolution crystal structure of MC159, a v-FLIP derived from the molluscum contagiosum virus, which is a member of the human poxvirus family. Unexpectedly, the two tandem death effector domains (DEDs) of MC159 rigidly associate with each other through a hydrophobic interface. Structure-based sequence analysis suggests that this interface is conserved in the tandem DEDs from other v-FLIP, c-FLIPS, and caspase-8 and -10. Strikingly, the overall packing arrangement between the two DEDs of MC159 resembles that between the caspase recruitment domains of Apaf-1 and caspase-9. In addition, each DED of MC159 contains a highly conserved binding motif on the surface, to which loss-of-function mutations in MC159 map. These observations, in conjunction with published evidence, reveal significant insights into the function of v-FLIP and suggest a mechanism by which v-FLIP and c-FLIPS inhibit death receptor signaling.
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PMID:Crystal structure of a viral FLIP: insights into FLIP-mediated inhibition of death receptor signaling. 1631

Expression of a prion-like protein, doppel, induces apoptosis-like changes in cerebellar neuronal granule and Purkinje cells of prion-knockout mice and this effect can be rescued by re-introduction of cellular prion. Since most of those studies were done in transgenic mice, in the present study, we have established a murine neuro-2a cell line and the primary rat adult reactive astrocyte model for studying doppel-induced apoptosis and possible prion counteraction. We demonstrate that expression of doppel in neuro-2a cells causes apoptosis, during which DNA fragmentation occurs as visualized by terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling staining and other intracellular changes characteristic of apoptosis are observed in the electron microscope. Using immunoblot analyses, we further demonstrate that doppel expression activates caspase-10 as well as caspase-3, but does not activate caspase-9. Addition of purified doppel to cultures of neuro-2a cells and the primary astrocytes causes similar apoptotic changes. Significantly, apoptosis induced by doppel is enhanced when cellular prion protein is depleted by RNA interference, suggesting a protective effect of cellular prion against doppel-induced apoptosis. The antagonistic interaction between cellular prion and doppel appears to involve direct protein-protein interaction possibly on cell membrane as cellular prion and doppel physically interact with each other and co-localize on cell membranes. Together, our data show that doppel induces apoptosis in neuroblastoma neuro-2a and rat primary astrocytes via a caspase-10 mediated pathway and that this effect is counteracted by cellular prion through direct interaction with doppel possibly on cell membrane.
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PMID:Doppel-induced apoptosis and counteraction by cellular prion protein in neuroblastoma and astrocytes. 1676 27

Anticancer drugs can induce tumor cell death by caspase-dependent apoptosis. The observation that procaspase-10 expression decreased in leukemic cells from acute myeloblastic leukemia patients at first relapse led us to explore the role of caspase-10 in cytotoxic drug-induced apoptosis. We show that caspase-10 is activated in etoposide-treated cells in a dose- and time-dependent manner. A caspase-10 peptide inhibitor, a caspase-10 dominant-negative mutant or a small interfering RNA (siRNA)-mediated downregulation of the enzyme negatively interfere with drug-induced cell death and caspase-2, -3, -8 and -9 activation. The extrinsic pathway to apoptosis is not involved in drug-induced caspase-10 activation that occurs downstream of Bax redistribution to mitochondria and cytochrome c release from this organelle. siRNA-mediated downregulation of Apaf-1 prevents etoposide-mediated activation of caspase-10. In a cell-free assay, cytochrome c and dATP treatment of cell extracts after immunodepletion of either caspase-3 or caspase-9 indicates that caspase-10 is activated downstream of caspase-9. Then, caspase-10 is involved in a feedback amplification loop that amplifies caspase-9 and -3 activities. Altogether, these data indicate an active role for caspase-10 in cytotoxic drug-induced tumor cell death, downstream of the mitochondria.
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PMID:Caspase-10 involvement in cytotoxic drug-induced apoptosis of tumor cells. 1676 58

15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), the terminal derivative of the PGJ series, is emerging as a potent antineoplastic agent among cyclopentenone prostaglandins derivatives and also known as the endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARgamma). On the other hand, death receptor 5 (DR5) is a specific receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is one of the most promising candidates for new cancer therapeutics. Here, we report that 15d-PGJ(2) induces DR5 expression at both mRNA and protein levels, resulting in the synergistic sensitization of TRAIL-induced apoptosis in human neoplastic cells, such as Jurkat human leukemia cells or PC3 human prostate cancer cells. 15d-PGJ(2) significantly increased DR5 mRNA stability, whereas it did not activate DR5 promoter activity. Synthetic PPARgamma agonists, such as pioglitazone or rosiglitazone, did not mimic the DR5-inducing effects of 15d-PGJ(2), and a potent PPARgamma inhibitor GW9662 failed to block DR5 induction by 15d-PGJ(2), suggesting PPARgamma-independent mechanisms. Cotreatment with 15d-PGJ(2) and TRAIL enhanced the sequential activation of caspase-8, caspase-10, caspase-9, caspase-3, and Bid. DR5/Fc chimera protein, zVAD-fmk pancaspase inhibitor, and caspase-8 inhibitor efficiently blocked the activation of these apoptotic signal mediators and the induction of apoptotic cell death enhanced by cotreatment with 15d-PGJ(2) and TRAIL. Moreover, a double-stranded small interfering RNA targeting DR5 gene, which suppressed DR5 up-regulation by 15d-PGJ(2), significantly attenuated apoptosis induced by cotreatment with 15d-PGJ(2) and TRAIL. These results suggest that 15d-PGJ(2) is a potent sensitizer of TRAIL-mediated cancer therapeutics through DR5 up-regulation.
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PMID:15-Deoxy-Delta12,14-prostaglandin J(2) induces death receptor 5 expression through mRNA stabilization independently of PPARgamma and potentiates TRAIL-induced apoptosis. 1689 69

Adrenomedullin 2 (ADM2) is a recently discovered member of the calcitonin/calcitonin gene-related peptide family with an exon-intron structure similar to that of ADM. The mRNA of ADM2 is expressed in several tissues, including uterus and ovary. The present study was designed to assess the effects of ADM2 antagonist (ADM2(17-47)) infusion to pregnant rats on fetal and placental growth. On Day 15 of gestation, rats were implanted s.c. with osmotic minipumps delivering 50 and 200 mug per rat per day of ADM2(17-47) and were killed on Gestational Day 18. In ADM2(17-47)-treated rats, placental weights were significantly inhibited in a dose-related manner, with an 11% reduction in the group of rats receiving 200 microg/day, whereas the fetal weights were reduced by 17% without significant differences between the two doses. 2 In ADM2(17-47)-infused rats, increased apoptosis was demonstrated in the labyrinth and junctional zones of rat placenta by the TUNEL method compared with the control animals. Western blot analysis demonstrated that in ADM2(17-47)-treated rats Bcl-2, mitochondrial cytochrome c, and active caspase-9 and caspase-3 were significantly increased compared with the controls. No significant treatment-associated changes were observed in Bax, Bid, p53, and caspase-8 and caspase-10 proteins in the treated placentas. In addition, infusion of ADM2(17-47) caused a significant decline in the transcripts of nitric oxide synthase 3 (NOS3) and NOS2. These findings show that ADM2(17-47) infusion in rats during midpregnancy cause fetoplacental growth restriction through the activation of mitochondrial apoptotic pathways. This study demonstrates for the first time (to our knowledge) a potential role for ADM2 in placental functions during pregnancy.
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PMID:Adrenomedullin 2 antagonist infusion to rats during midgestation causes fetoplacental growth restriction through apoptosis. 1697 58

Taxane derivatives such as paclitaxel elicit their antitumor effects at least in part by induction of apoptosis, but the underlying mechanisms are incompletely understood. Here, we used different cellular models with deficiencies in key regulators of apoptosis to elucidate the mechanism of paclitaxel-induced cell death. Apoptosis by paclitaxel was reported to depend on the activation of the initiator caspase-10; however, we clearly demonstrate that paclitaxel kills murine embryonic fibroblasts (MEFs) devoid of caspase-10 as well as human tumor cell lines deficient in caspase-10, caspase-8, or Fas-associating protein with death domain. In contrast, the lack of Apaf-1 or caspase-9, key regulators of the mitochondrial pathway, not only entirely protected against paclitaxel-induced apoptosis but could even confer clonogenic survival, depending on the cell type and drug concentration. Thus, paclitaxel triggers apoptosis not through caspase-10, but via caspase-9 activation at the apoptosome. This conclusion is supported by the fact that Bcl-2-overexpressing cells and Bax/Bak doubly-deficient MEFs were entirely resistant to paclitaxel-induced apoptosis. Interestingly, also the single knockout of Bim or Bax, but not that of Bak or Bid, conferred partial resistance, suggesting a particular role of these mediators in the cell-death pathway activated by paclitaxel.
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PMID:Apaf-1 and caspase-9 deficiency prevents apoptosis in a Bax-controlled pathway and promotes clonogenic survival during paclitaxel treatment. 1765 22

The novel cyclopenta[b]benzofuran, silvestrol, isolated from the fruits and twigs of Aglaia foveolata, has been found to exhibit very potent in vitro cytotoxic activity against several human cancer cell lines. Furthermore, it was active in the in vivo P388 murine leukemia model. In this study, the mechanism of cytotoxicity mediated by silvestrol in the LNCaP (hormone-dependent human prostate cancer) cell line was investigated. Silvestrol induced an apoptotic response, disrupted the mitochondrial trans-membrane potential and caused cytochrome c release into the cytoplasm. Immunoblot analysis indicated that, at the protein level, silvestrol produced an increase of Bcl-xl phosphorylation with a concomitant increase of bak. Furthermore, caspase-2, -9 and -10 appeared to be involved in silvestrol-mediated apoptosis. In contrast, the involvement of caspase-3 and -7 was not detected, either by immunoblot or caspase-3/-7-like activity analysis, indicating that these pathways do not play a crucial role in silvestrol-induced apoptosis. To investigate the relative contribution of the caspases, inhibition of apoptosis with four different cell-permeable inhibitors was studied (Boc-D-Fmk, Z-VDVAD-FMK Z-LEHD-FMK and Z-AEVD-FMK). Only the general caspase inhibitor, Boc-D-Fmk, completely inhibited the formation of apoptotic bodies. In contrast, caspase-2 and caspase-9 selective inhibitors induced about a 40% reduced apoptotic response, whereas the caspase-10 selective inhibitor caused about a 60% reduction in apoptosis compared to silvestrol only treated cells. Taken together, the studies described herein demonstrate the involvement of the apoptosome/mitochondrial pathway and suggest the possibility that silvestrol may also trigger the extrinsic pathway of programmed cell death signaling in tumor cells.
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PMID:Silvestrol, a potential anticancer rocaglate derivative from Aglaia foveolata, induces apoptosis in LNCaP cells through the mitochondrial/apoptosome pathway without activation of executioner caspase-3 or -7. 1769 1

Our study has shown that the Amaryllidaceae isocarbostyril narciclasine induces marked apoptosis-mediated cytotoxic effects in human cancer cells but not in normal fibroblasts by triggering the activation of the initiator caspases of the death receptor pathway (caspase-8 and caspase-10) at least in human MCF-7 breast and PC-3 prostate carcinoma cells. The formation of the Fas and death receptor 4 (DR4) death-inducing signaling complex was clearly evidenced in MCF-7 and PC-3 cancer cells. Caspase-8 was found to interact with Fas and DR4 receptors on narciclasine treatment. However, narciclasine-induced downstream apoptotic pathways in MCF-7 cells diverged from those in PC-3 cells, where caspase-8 directly activated effector caspases such as caspase-3 in the absence of any further release of mitochondrial proapoptotic effectors. In contrast, in MCF-7 cells, the apoptotic process was found to require an amplification step that is mitochondria-dependent, with Bid processing, release of cytochrome c, and caspase-9 activation. It is postulated that the high selectivity of narciclasine to cancer cells might be linked, at least in part, to this activation of the death receptor pathway. Normal human fibroblasts appear approximately 250-fold less sensitive to narciclasine, which does not induce apoptosis in these cells probably due to the absence of death receptor pathway activation.
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PMID:The Amaryllidaceae isocarbostyril narciclasine induces apoptosis by activation of the death receptor and/or mitochondrial pathways in cancer cells but not in normal fibroblasts. 1789 72

Synthetic triterpenoids 2-cyano-3, 12-dioxooleana-1, 9-(11)-dien-28-oic acid (CDDO) and CDDO-Me (CDDO-methyl ester) have entered clinical trials for cancer. We determined that CDDO analogues at submicromolar concentrations induce apoptosis of cultured prostate cancer cell lines, LNCaP, ALVA31, Du145, PC3, and PPC1, with lethal dose 50% approximately 1 micromol/L for CDDO-Me and an imidazole analogue (CDDO-Im). These compounds induced apoptosis of prostate cancer cells as characterized by cleavage of caspase-3, caspase-7, caspase-8, caspase-9, caspase-10, BID, and poly(ADP)ribose polymerase and by dependence on caspase activity. Moreover, triterpenoid-induced cell death was abolished by caspase-8-targeting small interfering (si) RNA. To explore the mechanism(s) involved in caspase-8 activation, we examined cell surface expression of death receptor (DR)4 and DR5 after triterpenoid treatment. Cell surface DR4 and DR5 expression was significantly up-regulated by CDDO or CDDO-Im but not by CDDO-Me. DR4 and DR5 knockdown with siRNA significantly inhibited apoptosis induced by CDDO and CDDO-Im but had no effect on CDDO-Me-induced killing, suggesting that CDDO and CDDO-Im induce apoptosis by a different mechanism than CDDO-Me. In addition to activating the caspase-8-dependent extrinsic apoptosis pathway, we observed that Bcl-X(L) overexpression inhibited triterpenoid-mediated killing of prostate cancer cell line Du145, suggesting that the intrinsic pathway (via mitochondria) also participates in triterpenoid-mediated killing. In vivo antitumor activity of CDDO-Me was shown using a Du145 tumor xenograft model in nude rats. Altogether, these findings suggest CDDO and related synthetic triterpenoids should be further evaluated as potential novel therapeutics for hormone refractory prostate cancers.
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PMID:Apoptotic activity and mechanism of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic-acid and related synthetic triterpenoids in prostate cancer. 1841 62

Paclitaxel, a natural product originally isolated from Taxus brevifolia, belongs to the most successful anticancer drugs. Nevertheless, its poor water solubility represents a considerable disadvantage in clinical use, and novel derivatives with improved pharmacological features are required. We isolated 7-xylosyl-10-deacetylpaclitaxel from Taxus chinensis, which reveals higher water solubility than paclitaxel. This compound induced mitotic cell cycle arrest and apoptosis as measured by flow cytometry, DNA laddering, and transmission electron microscopy. Pro-apoptotic Bax and Bad protein expression was up-regulated and anti-apoptotic Bcl-2 and Bcl-XL expression down-regulated, which lead to a disturbance of the mitochondrial membrane permeability and to the activation of caspase-9. In turn, caspase-9 activated downstream caspases-3 and -6, but not caspase-8. Bid was also activated by caspase-3. Reversely, treatment with a caspase-10-specific inhibitor could not protect PC-3 cells from 7-xylosyl-10-deacetyl-paclitaxel-triggered apoptosis. Moreover, 7-xylosyl-10-deacetylpaclitaxel had no effect on the expression of CD95 and NF-kappaB proteins, indicating that apoptosis was induced through the mitochondrial-dependent pathway in PC-3 cells.
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PMID:Activation of the mitochondria-driven pathway of apoptosis in human PC-3 prostate cancer cells by a novel hydrophilic paclitaxel derivative, 7-xylosyl-10-deacetylpaclitaxel. 1857 55


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