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)

Little is known on how cancer cells can acquire resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In this study, we established TRAIL-resistant cells from the TRAIL-sensitive human ovarian carcinoma cell line OVCAR3 to evaluate the potential mechanisms of acquired resistance to TRAIL. The selected resistant cells were cross-resistant to Fas ligand but remained sensitive to drug-induced apoptosis. Expression of TRAIL receptors was not altered in TRAIL-resistant OVCAR3 cells. Cleavage of caspase-8 and caspase-3 occurred in both TRAIL-resistant and TRAIL-sensitive cells. However, mature caspase-3 fragments were not detected by immunoblot in TRAIL-resistant cells and caspase-3 activity was significantly inhibited in these cells. The addition of proteasome inhibitors significantly increased TRAIL-induced apoptosis in resistant cells and enhanced the accumulation of mature caspase-3 fragments. Pretreatment with cycloheximide showed that active caspase-3 fragments have a high turnover rate in OVCAR3 R350 cells. X-linked inhibitor of apoptosis down-regulation by RNA interference also increased the accumulation of cleaved caspase-3 intermediates and resensitized TRAIL-resistant cells. Our findings show that altered turnover of mature caspase-3 may lead to acquired TRAIL resistance in ovarian cancer cells. Proteasome and X-linked inhibitor of apoptosis inhibitors could have a role in clinical situations to potentiate the cytotoxic effects of TRAIL in resistant tumor cells.
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PMID:Acquired resistance to TRAIL-induced apoptosis in human ovarian cancer cells is conferred by increased turnover of mature caspase-3. 1654 65

The proteasome inhibitors are a new class of antitumor agents. These inhibitors cause the accumulation of many proteins in the cell with the induction of apoptosis including TRAIL death receptors DR4 and DR5, but the role of the TRAIL apoptotic pathway in proteasome inhibitor cytotoxicity is unknown. Herein, we have demonstrated that the induction of apoptosis by the proteasome inhibitors, MG-132 and PS-341 (bortezomib, Velcade), in primary CLL cells and the Burkitt lymphoma cell line, BJAB, is associated with up-regulation of TRAIL and its death receptors, DR4 and DR5. In addition, FLICE-like inhibitory protein (c-FLIP) protein is decreased. MG-132 treatment increases binding of DR5 to the adaptor protein FADD, and causes caspase-8 activation and cleavage of pro-apoptotic BID. Moreover, DR4:Fc or blockage of DR4 and DR5 expression using RNA interference, which prevents TRAIL apoptotic signaling, blocks proteasome inhibitor induced apoptosis. MG-132 also increases apoptosis and DR5 expression in normal B-cells. However, when the proteasome inhibitors are combined with TRAIL or TRAIL receptor activating antibodies the amount of apoptosis is increased in CLL cells but not in normal B cells. Thus, activation of the TRAIL apoptotic pathway contributes to proteasome inhibitor induced apoptosis in CLL cells.
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PMID:The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells. 1669 49

Certain members of the thiazolidinedione (TZD) family of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, such as troglitazone and ciglitazone, exhibit antitumor activities; however, the underlying mechanism remains inconclusive. Substantial evidence suggests that the antiproliferative effect of these TZD members in cancer cells is independent of PPARgamma activation. To discern the role of PPARgamma in the antitumor effects of TZDs, we have synthesized PPARgamma-inactive TZD analogs which, although devoid of PPARgamma activity, retain the ability to induce apoptosis with a potency equal to that of their parental TZDs in cancer cell lines with varying PPARgamma expression status. Mechanistic studies from this and other laboratories have further suggested that troglitazone and ciglitazone mediate antiproliferative effects through a complexity of PPARgamma-independent mechanisms. Evidence indicates that troglitazone and ciglitazone block BH3 domain-mediated interactions between the anti apoptotic Bcl-2 (B-cell leukemia/lymphoma 2) members Bcl-2/Bcl-xL and proapoptotic Bcl-2 members. Moreover, these TZDs facilitate the degradation of cyclin D1 and caspase-8-related FADD-like IL-l-converting enzyme (FLICE)-inhibitory protein through proteasome-mediated proteolysis, and down-regulate the gene expression of prostate-specific antigen gene expression by inhibiting androgen activation of the androgen response elements in the promoter region. More importantly, dissociation of the effects of TZDs on apoptosis from their original pharmacological activity (i.e. PPARgamma activation) provides a molecular basis for the exploitation of these compounds to develop different types of molecularly targeted anticancer agents. These TZD-derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment.
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PMID:Beyond peroxisome proliferator-activated receptor gamma signaling: the multi-facets of the antitumor effect of thiazolidinediones. 1672 70

The cyclin-dependent kinase inhibitor flavopiridol is undergoing clinical trials as an antitumor drug. We show here that pretreatment of different human breast cancer cell lines with flavopiridol facilitates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. In breast tumor cells, apoptosis induction by TRAIL is blocked at the level of apical caspase-8 activation. Flavopiridol treatment enhances TRAIL-induced formation of death-inducing signaling complex and early processing of procaspase-8. Subsequently, a TRAIL-induced, mitochondria-operated pathway of apoptosis is activated in cells treated with flavopiridol. Down-regulation of cellular FLICE-inhibitory proteins (c-FLIP; c-FLIP(L) and c-FLIP(S)) is observed on flavopiridol treatment. c-FLIP loss and apoptosis sensitization by flavopiridol are both prevented in cells treated with an inhibitor of the ubiquitin-proteasome system. Furthermore, targeting c-FLIP directly with small interfering RNA oligonucleotides also sensitizes various human breast tumor cell lines to TRAIL-induced apoptosis. Our results indicate that flavopiridol sensitizes breast cancer cells to TRAIL-induced apoptosis by facilitating early events in the apoptotic pathway, and this combination treatment could be regarded as a potential therapeutic tool against breast tumors.
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PMID:Flavopiridol induces cellular FLICE-inhibitory protein degradation by the proteasome and promotes TRAIL-induced early signaling and apoptosis in breast tumor cells. 1695 Dec 3

The synergistic interaction between proteasome inhibitors and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising approach to induce cell death in tumor cells. However, the molecular and biochemical mechanisms of this synergism have been proven to be cell type specific. We therefore focused our investigation on TRAIL-resistant colon carcinoma cells in this study. DNA fragmentation, mitochondrial membrane depolarization and increased caspase-3-like enzyme activity was exclusively induced only by combined treatment with proteasome inhibitors (epoxomicin, MG132, bortezomib/PS-341) and TRAIL. The expression level of anti-apoptotic proteins (XIAP, survivin, Bcl-2, Bcl-XL), regulated by NF-kappaB transcription factor, was not effected by any of these treatments. TRAIL alone induced only partial activation of caspase-3 (p20), while the combination of TRAIL and proteasome inhibition led to the full proteolytic activation of caspase-3 (p17). Only the combination treatment induced marked membrane depolarization and the release of cytochrome c, HtrA2/Omi and Smac/DIABLO. Apoptosis-inducing factor (AIF) was not released in any of these conditions. These results are consistent with a model where the full activation of caspase-3 by caspase-8 is dependent on the release of Smac/DIABLO in response to the combined treatment. This molecular mechanism, independent of the inhibition NF-kappaB activity, may provide rationale for the combination treatment of colon carcinomas with proteasome inhibitors and recombinant TRAIL or agonistic antibody of TRAIL receptors.
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PMID:Proteasome inhibitors sensitize colon carcinoma cells to TRAIL-induced apoptosis via enhanced release of Smac/DIABLO from the mitochondria. 1699 92

Second mitochondria-derived activator of caspases (Smac) promotes apoptosis via activation of caspases. Here we show that a low-molecular-weight Smac mimetic LBW242 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib therapies. Examination of purified patient MM cells demonstrated similar results, without significant cytotoxicity against normal lymphocytes and bone marrow stromal cells (BMSCs). Importantly, LBW242 abrogates paracrine MM cell growth triggered by their adherence to BMSCs and overcomes MM cell growth and drug-resistance conferred by interleukin-6 or insulinlike growth factor-1. Overexpression of Bcl-2 similarly does not affect LBW242-induced cytotoxicity. Mechanistic studies show that LBW242-induced apoptosis in MM cells is associated with activation of caspase-8, caspase-9, and caspase-3, followed by PARP cleavage. In human MM xenograft mouse models, LBW242 is well tolerated, inhibits tumor growth, and prolongs survival. Importantly, combining LBW242 with novel agents, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the proteasome inhibitors bortezomib and NPI-0052, as well as with the conventional anti-MM agent melphalan, induces additive/synergistic anti-MM activity. Our study therefore provides the rationale for clinical protocols evaluating LBW242, alone and together with other anti-MM agents, to improve patient outcome in MM.
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PMID:Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM). 1703 24

The pro-apoptotic death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received significant attention as a novel cancer therapeutic, since it selectively induces apoptosis in malignant and not normal cells. Unfortunately, prostate cancer cells display little if any susceptibility to TRAIL-induced apoptosis. However, sensitivity to TRAIL is enhanced by doxorubicin, which correlated with a decrease in expression of the caspase-8 inhibitor cFLIP (Kelly et al., Cancer Biol Ther 1:520). In this study we show that doxorubicin induces a time- and dose-dependent loss of cFLIP protein, but does not affect steady-state mRNA levels. Proteasome inhibition stabilized cFLIPL in the presence of doxorubicin. Although proteasome inhibitors increased basal levels of short cFLIP isoforms, cFLIPS declined at a similar rate in the absence or presence of proteasome inhibition during doxorubicin treatment. Ectopic expression of a cFLIPSGFP fusion protein protected PC3 cells from TRAIL-induced apoptosis in the absence or presence of doxorubicin, whereas downregulation of cFLIPS by RNA interference resulted in sensitization to TRAIL-induced apoptosis. We conclude that doxorubicin-mediated downregulation of cFLIPS, which occurs at the post-transcriptional level independent of proteasome-mediated pathways, is sufficient to enhance TRAIL sensitivity in PC3 prostate carcinoma cells.
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PMID:Targeting the short form of cFLIP by RNA interference is sufficient to enhance TRAIL sensitivity in PC3 prostate carcinoma cells. 1710 51

Several combined strategies have been recently proposed to overcome the resistance to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) showed by some tumor cells, thus improving the use of this death ligand in antitumor therapy. However, the molecular mechanisms of the tumor selective activity of TRAIL are not completely understood and hence the effects of the combined therapy on normal cells are unknown. Here, we have studied the resistance of primary T lymphocytes to TRAIL-mediated apoptosis. No significant differences were found in the expression of proteins involved in TRAIL-mediated apoptosis between resting and activated T cells. The low expression of death receptors TRAIL-R1/-R2 as well as the high levels of the antiapoptotic proteins TRAIL-R4 and cellular Fas-associated death domain-like IL-1beta-converting enzyme-inhibitory protein (c-FLIP) may explain the lack of caspase-8 activation observed upon TRAIL treatment in both cell types. We have also analyzed the effect of different sensitizing agents such as genotoxic drugs, phosphatidylinositol-3 kinase (PI3K) inhibitors, proteasome inhibitors, microtubule depolymerizing agents, histone deacetylase inhibitors (HDACi), and NF-kappaB inhibitors. Although some of them induced T cell death, only NF-kappaB inhibitors sensitized activated T cells to TRAIL-induced apoptosis, maybe through the regulation of the antiapoptotic proteins TRAIL-R4, c-FLIP(S) and members of the inhibitors of apoptosis proteins (IAP) family. These results question the safety of the combined treatments with TRAIL and NF-kappaB inhibitors against tumors.
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PMID:Regulation of the resistance to TRAIL-induced apoptosis in human primary T lymphocytes: role of NF-kappaB inhibition. 1725 81

The COP9 signalosome is a large multiprotein complex that consists of eight subunits termed CSN1-CSN8. The diverse functions of the COP9 complex include regulation of several important intracellular pathways, including the ubiquitin/proteasome system, DNA repair, cell cycle, developmental changes, and some aspects of immune responses. Nod1 is also thought to be an important cytoplasmic receptor involved in innate immune responses. It detects specific motifs of bacterial peptidoglycan, and this results in activation of multiple signaling pathways and changes in cell function. In this report, we performed a yeast two-hybrid screening and discovered that Nod1 interacts with several components of the COP9 signalosome through its CARD domain. Moreover, we observed that activation of the Nod1 apoptotic pathway leads to specific cleavage of the subunit CSN6. This cleavage is concomitant with caspase processing and generates a short amino-terminal peptide of 3 kDa. A complete inhibition of this cleavage was achieved in the presence of the broad spectrum pharmacological inhibitor of apoptosis, Z-VAD. Furthermore, overexpression of CLARP, a specific caspase 8 inhibitor, completely blocked cleavage of CSN6. Taken together, these results suggest a critical role of caspase 8 in the processing of CSN6. Moreover, these findings suggest that CSN6 cleavage may result in modifications of functions of the COP9 complex that are involved in apoptosis.
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PMID:The subunit CSN6 of the COP9 signalosome is cleaved during apoptosis. 1733 51

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


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