Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human neuroblastomas possess several mechanisms of self-defense that may confer an ability to resist apoptosis and contribute to the observed difficulty in treating these tumors in the clinical setting. These molecular alterations may include defects in proapoptotic genes as well as the overexpression of prosurvival factors, such as Akt among others. As a key regulator of the turnover of proteins that modulate the cell cycle and mechanisms of apoptosis, the proteasome could serve as an important target for the treatment of neuroblastoma. The present studies provide the first evidence that bortezomib, a newly approved inhibitor of proteasome function, inhibits phosphorylation of Akt, induces the translocation of proapoptotic Bid, and potently enhances the apoptosis of murine neuroblastoma tumor cells in vitro. Furthermore, in that inhibitors of the Akt pathway can sensitize otherwise resistant TBJ/Neuro-2a cells to apoptosis induced by IFN-gamma plus TNF-alpha, we hypothesized that bortezomib also could sensitize these cells to IFN-gamma plus TNF-alpha. We demonstrate for the first time that bortezomib not only up-regulates the expression of receptors for IFN-gamma and TNF-alpha on both TBJ neuroblastoma and EOMA endothelial cell lines, but also markedly enhances the sensitivity of these cells to apoptosis induced by IFN-gamma plus TNF-alpha in vitro. Furthermore, bortezomib enhances the in vivo antitumor efficacy of IFN-gamma/TNF-alpha-inducing cytokines, including both IL-2 and IL-12 in mice bearing well-established primary and/or metastatic TBJ neuroblastoma tumors. Collectively, these studies suggest that bortezomib could be used therapeutically to enhance the proapoptotic and overall antitumor activity of systemic cytokine therapy in children with advanced neuroblastoma.
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PMID:Proteasome inhibition to maximize the apoptotic potential of cytokine therapy for murine neuroblastoma tumors. 1667 Mar 42

Histone deacetylase (HDAC) inhibitors represent a promising group of anticancer agents. This paper shows that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) stimulated at 5-10 microM apoptosis in human hepatoma HepG2 and Huh6 cells, but was ineffective in primary human hepatocytes (PHH). In HepG2 cells SAHA induced the extrinsic apoptotic pathway, increasing the expression of both FasL and FasL receptor and causing the activation of caspase-8. Moreover, SAHA enhanced the level of Bim proteins, stimulated alternative splicing of the Bcl-X transcript with the expression of the proapoptotic Bcl-Xs isoform, induced degradation of Bid into the apoptotic factor t-Bid and dephosphorylation and inactivation of the anti-apoptotic factor Akt. Consequently, SAHA caused loss of mitochondrial transmembrane potential, release of cytochrome c from mitochondria, activation of caspase-3 and degradation of PARP. Interestingly, a combination of suboptimal doses of SAHA (1 microM) and bortezomib (5-10 nM), a potent inhibitor of 26S proteasome, synergistically induced apoptosis in both HepG2 and Huh6 cells, but was ineffective in PHH. Combined treatment increased with synergistic effects the expression levels of c-Jun, phospho-c-Jun and FasL and the production of Bcl-Xs. These effects were accompanied by activation of Bid, caspase-8 and 3. In conclusion, SAHA stimulated apoptosis in hepatoma cells and exerted a synergistic apoptotic effect when combined with bortezomib. In contrast, these treatments were quite ineffective in inducing apoptosis in PHH. Thus, our results suggest the potential application of the SAHA/bortezomib combination in clinical trials for liver cancer.
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PMID:SAHA induces apoptosis in hepatoma cells and synergistically interacts with the proteasome inhibitor Bortezomib. 1735 39

The platinum-based chemotherapeutic agent oxaliplatin displays a wide range of antitumor activities. However, the underlying molecular responses to oxaliplatin in esophageal cancer remain largely unknown. In the present study, we investigated the effect of oxaliplatin on two esophageal cancer cell lines, squamous cell carcinoma (TE3) and adenocarcinoma (TE7). Following cell-cycle arrest at G(2) phase after oxaliplatin treatment, TE3 cells died via apoptosis and TE7 cells died via mitotic catastrophe. Survivin was inhibited more in TE7 cells compared with TE3 cells, but inhibition of survivin using small interfering RNA induced mitotic catastrophe in both cell lines. Further investigations indicated that survivin promoter activity was also inhibited by oxaliplatin. Among mitotic catastrophe-associated proteins, 14-3-3 sigma was decreased in TE7 cells; no evident changes were observed for aurora kinases. Oxaliplatin-induced apoptosis in the TE3 cells was caspase dependent. However, downregulation of Bad, Bid, Puma, and Noxa, lack of cytochrome c release, and limited loss of mitochondrial membrane potential in early phase indicated possible initiation by pathways other than the mitochondrial pathway. Mechanistic studies showed that downregulation of survivin by oxaliplatin in TE7 cells was partially due to the proteasome-mediated protein degradation pathway and partially due to the downregulation of Sp1 transcription factor. Similar results were obtained for another gastric adenocarcinoma cell line, MKN45, in which survivin was previously shown to be inhibited by oxaliplatin. These data indicate that survivin may be a key target for oxaliplatin. The ability of oxaliplatin to induce different modes of cell death may contribute to its efficacy in esophageal cancer.
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PMID:Oxaliplatin induces mitotic catastrophe and apoptosis in esophageal cancer cells. 1794 50

Bcl-2 family member Bid is subject to autoinhibition; in the absence of stimuli, its N-terminal region sequesters the proapoptotic Bcl-2 homology 3 (BH3) domain. Upon proteolytic cleavage in its unstructured loop, Bid is activated, although structural data reveal no apparent resulting conformational change. We found that, upon Bid cleavage, the N-terminal fragment (tBid-N) is ubiquitinated and degraded, thus freeing the BH3 domain in the C-terminal fragment (tBid-C). Ubiquitination of tBid-N is unconventional because acceptor sites are neither lysines nor the N terminus. Chemical approaches implicated thioester and hydroxyester linkage of ubiquitin and mutagenesis implicated serine and possibly threonine as acceptor residues in addition to cysteine. Acceptor sites reside predominantly but not exclusively in helix 1, which is required for ubiquitination and degradation of tBid-N. Rescue of tBid-N from degradation blocked Bid's ability to induce mitochondrial outer membrane permeability but not mitochondrial translocation of the cleaved complex. We conclude that unconventional ubiquitination and proteasome-dependent degradation of tBid-N is required to unleash the proapoptotic activity of tBid-C.
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PMID:Apoptosis induction by Bid requires unconventional ubiquitination and degradation of its N-terminal fragment. 1816 54

When grown as three-dimensional structures, tumor cells can acquire an additional multicellular resistance to apoptosis that may mimic the chemoresistance found in solid tumors. We developed a multicellular spheroid model of malignant mesothelioma to investigate molecular mechanisms of acquired apoptotic resistance. We found that mesothelioma cell lines, when grown as multicellular spheroids, acquired resistance to a variety of apoptotic stimuli, including combinations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), ribotoxic stressors, histone deacetylase, and proteasome inhibitors, that were highly effective against mesothelioma cells when grown as monolayers. Inhibitors of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway, particularly rapamycin, blocked much of the acquired resistance of the spheroids, suggesting a key role for mTOR. Knockdown by small interference RNA of S6K, a major downstream target of mTOR, reproduced the effect of rapamycin, thereby confirming the role of mTOR and of S6K in the acquired resistance of three dimensional spheroids. Rapamycin or S6K knockdown increased TRAIL-induced caspase-8 cleavage in spheroids, suggesting initially that mTOR inhibited apoptosis by actions at the death receptor pathway; however, isolation of the apoptotic pathways by means of Bid knockdown ablated this effect showing that mTOR actually controls a step distal to Bid, probably at the level of the mitochondria. In sum, mTOR and S6K contribute to the apoptotic resistance of mesothelioma cells in three-dimensional, not in two-dimensional, cultures. The three-dimensional model may reflect a more clinically relevant in vitro setting in which mTOR exhibits anti-apoptotic properties.
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PMID:Mammalian target of rapamycin contributes to the acquired apoptotic resistance of human mesothelioma multicellular spheroids. 1833 27

Human epidermal growth factor receptor-2 (HER-2/ErbB2/neu), a receptor tyrosine kinase that is amplified/overexpressed in poor prognosis breast carcinomas, confers resistance to apoptosis by activating cell survival pathways. Here we demonstrate that the cytoplasmic tail of HER-2 is cleaved by caspases at Asp(1016)/Asp(1019) to release a approximately 47-kDa product, which is subsequently proteolyzed by caspases at Asp(1125) into an unstable 22-kDa fragment that is degraded by the proteasome and a predicted 25-kDa product. Both the 47- and 25-kDa products translocate to mitochondria, release cytochrome c by a Bcl-x(L)-suppressible mechanism, and induce caspase-dependent apoptosis. The 47- and 25-kDa HER-2 cleavage products share a functional BH3-like domain, which is required for cytochrome c release in cells and isolated mitochondria and for apoptosis induction. Caspase-cleaved HER-2 binds Bcl-x(L) and acts synergistically with truncated Bid to induce apoptosis, mimicking the actions of the BH3-only protein Bad. Moreover, the HER-2 cleavage products cooperate with Noxa to induce apoptosis in cells expressing both Bcl-x(L) and Mcl-1, confirming their Bad-like function. Collectively, our results indicate that caspases activate a previously unrecognized proapoptotic function of HER-2 by releasing a Bad-like cell death effector.
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PMID:Caspase cleavage of HER-2 releases a Bad-like cell death effector. 1842 May 86

Large granular lymphocyte (LGL) leukemia is a clonal proliferative disease of T and natural killer (NK) cells. Interleukin (IL)-15 is important for the development and progression of LGL leukemia and is a survival factor for normal NK and T memory cells. IL-15 alters expression of Bcl-2 family members, Bcl-2, Bcl-XL, Bim, Noxa, and Mcl-1; however, effects on Bid have not been shown. Using an adoptive transfer model, we show that NK cells from Bid-deficient mice survive longer than cells from wild-type control mice when transferred into IL-15-null mice. In normal human NK cells, IL-15 significantly reduces Bid accumulation. Decreases in Bid are not due to alterations in RNA accumulation but result from increased proteasomal degradation. IL-15 up-regulates the E3 ligase HDM2 and we find that HDM2 directly interacts with Bid. HDM2 suppression by short hairpin RNA increases Bid accumulation lending further support for HDM2 involvement in Bid degradation. In primary leukemic LGLs, Bid levels are low but are reversed with bortezomib treatment with subsequent increases in LGL apoptosis. Overall, these data provide a novel molecular mechanism for IL-15 control of Bid that potentially links this cytokine to leukemogenesis through targeted proteasome degradation of Bid and offers the possibility that proteasome inhibitors may aid in the treatment of LGL leukemia.
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PMID:Interleukin-15 enhances proteasomal degradation of bid in normal lymphocytes: implications for large granular lymphocyte leukemias. 1936 3

TP-110, a new proteasome inhibitor, has previously shown potent growth inhibition in various tumor cell lines. In this study, the mechanism of TP-110-induced apoptosis is investigated in a human multiple myeloma cell line. Treatment with TP-110 for 24 h in vitro induced apoptosis in multiple myeloma cell line RPMI8226. Although the expression of Bcl-2, Bcl-xL and Bax was not affected by the treatment of TP-110, cleavage of Bid and release of cytochrome c were enhanced. Interestingly, TP-110 reduced the intrinsic inhibitor of apoptosis proteins (IAPs), cIAP-1 and XIAP, that suppress executioner caspases. The reduction of IAPs was observed not only by TP-110, but also by another proteasome inhibitor, MG-132. These results indicate that proteasome inhibitors reduce the level of IAPs and that the apoptosis induced by TP-110 is correlated with the level of IAPs in leukemia cell lines. Additionally, a reduction of cIAP-1 and XIAP by TP-110 contributes to the sensitization of Fas-mediated apoptosis. Taken together, the alteration of the apoptosis regulatory proteins by a proteasome inhibitor induces apoptosis in tumor cells.
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PMID:TP-110, a new proteasome inhibitor, down-regulates IAPs in human multiple myeloma cells. 1941 35

Apoptosis in Xenopus egg extracts is carried out by maternally stockpiled materials, but the contributions of endogenous apoptosis regulators are still poorly characterized. Here we examined the physiological role of Xenopus Bid (xBid), a pro-apoptotic BH3-only member of Bcl-2 family proteins. We found that endogenous xBid was a physiological accelerator of apoptosis in egg extracts. Interestingly, xBid was mono-/diubiquitylated but not degraded by proteasome in egg extracts, and we identified three ubiquitylated Lys residues in the N-terminal propeptide region. Comparison with human Bid suggested that mono-/diubiquitylation is a specific feature of xBid.
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PMID:Pro-apoptotic activity and mono-/diubiquitylation of Xenopus Bid in egg extracts. 1942 13

In this study, we investigated the biological effects of heteronemin, a marine sesterterpene isolated from the sponge Hyrtios sp. on chronic myelogenous leukemia cells. To gain further insight into the molecular mechanisms triggered by this compound, we initially performed DNA microarray profiling and determined which genes respond to heteronemin stimulation in TNFalpha-treated cells and which genes display an interaction effect between heteronemin and TNFalpha. Within the differentially regulated genes, we found that heteronemin was affecting cellular processes including cell cycle, apoptosis, mitogen-activated protein kinases (MAPKs) pathway and the nuclear factor kappaB (NF-kappaB) signaling cascade. We confirmed in silico experiments regarding NF-kappaB inhibition by reporter gene analysis, electrophoretic mobility shift analysis and I-kappaB degradation. In order to assess the underlying molecular mechanisms, we determined that heteronemin inhibits both trypsin and chymotrypsin-like proteasome activity at an IC(50) of 0.4 microM. Concomitant to the inhibition of the NF-kappaB pathway, we also observed a reduction in cellular viability. Heteronemin induces apoptosis as shown by annexin V-FITC/propidium iodide-staining, nuclear morphology analysis, pro-caspase-3, -8 and -9 and poly(ADP-ribose) polymerase (PARP) cleavage as well as truncation of Bid. Altogether, results show that this compound has potential as anti-inflammatory and anti-cancer agent.
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PMID:Heteronemin, a spongean sesterterpene, inhibits TNF alpha-induced NF-kappa B activation through proteasome inhibition and induces apoptotic cell death. 1981 97


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