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)

In the present study we have explored the sensitivity of ovarian cancer cells to TRAIL and proteasome inhibitors. Particularly, we have explored the capacity of proteasome inhibitors to bypass TRAIL resistance of ovarian cancer cells. For these studies we have used the A2780 ovarian cancer cell line and its chemoresistant derivatives A2780/DDP and A2780/ADR, providing evidence that: (i) the three cell lines are either scarcely sensitive (A2780 and A2780/ADR) or moderately sensitive (A2780/DDP) to the cytotoxic effects of TRAIL; (ii) the elevated c-FLIP expression observed in ovarian cancer cells is a major determinant of TRAIL resistance of these cells; (iii) proteasome inhibitors (PS-341 or MG132) are able to exert a significant pro-apoptotic effect and to greatly enhance the sensitivity of both chemosensitive and chemoresistant A2780 cells to TRAIL; (iv) proteasome inhibitors damage mitochondria through stabilization of BH3-only proteins, Bax and caspase activation and significantly enhance TRAIL-R2 expression; (v) TRAIL-R2, but not TRAIL-R1, mediates the apoptotic effects of TRAIL on ovarian cancer cells. Importantly, studies on primary ovarian cancer cells have shown that these cells are completely resistant to TRAIL and proteasome inhibitors markedly enhance the sensitivity of these cells to TRAIL. Given the high susceptibility of ovarian cancer cells to proteasome inhibitors, our results further support the experimental use of these compounds in the treatment of ovarian cancer.
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PMID:Proteasome inhibitors sensitize ovarian cancer cells to TRAIL induced apoptosis. 1725 98

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent because it induces apoptosis in cancer cells but not in normal cells. Unfortunately, some cancer cells develop resistance to TRAIL-induced apoptosis. Therefore, it is clinically relevant to determine the molecular mechanisms that differentiate between TRAIL-sensitive and TRAIL-resistant tumors. Previously, we have shown that the antiapoptotic molecule cellular-FLICE-inhibitory protein long isoform [c-FLIP(L)] is necessary and sufficient to maintain resistance to TRAIL-induced apoptosis. We have found that c-FLIP(L) is transcriptionally regulated by the activator protein-1 (AP-1) family member protein c-Fos. Here, we report that MG-132, a small-molecule inhibitor of the proteasome, sensitizes TRAIL-resistant prostate cancer cells by inducing c-Fos and repressing c-FLIP(L). c-Fos, which is activated by MG-132, negatively regulates c-FLIP(L) by direct binding to the putative promoter region of the c-FLIP(L) gene. In addition to activating c-Fos, MG-132 activates another AP-1 family member, c-Jun. We show that c-Fos heterodimerizes with c-Jun to repress transcription of c-FLIP(L). Therefore, MG-132 sensitizes TRAIL-resistant prostate cancer cells by activating the AP-1 family members c-Fos and c-Jun, which, in turn, repress the antiapoptotic molecule c-FLIP(L).
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PMID:MG-132 sensitizes TRAIL-resistant prostate cancer cells by activating c-Fos/c-Jun heterodimers and repressing c-FLIP(L). 1733 55

The novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me) induces apoptosis of cancer cells, enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, and exhibits potent anticancer activity in animal models with a favorable pharmacokinetic profile. Thus, CDDO-Me is being tested in Phase I clinical trials. In an effort to understand the mechanism by which CDDO-Me induces apoptosis, particularly in human lung cancer cells, we previously demonstrated that CDDO-Me induces apoptosis involving c-Jun N-terminal kinase (JNK)-dependent upregulation of death receptor 5 (DR5) expression. In the current work, we determined the modulatory effects of CDDO-Me on the levels of c-FLIP, a major inhibitor of death receptor-mediated caspase-8 activation, and its impact on CDDO-Me-induced apoptosis and enhancement of TRAIL-induced apoptosis in human lung cancer cells. CDDO-Me rapidly and potently decreased c-FLIP levels including both long (FLIP(L)) and short (FLIP(S)) forms of c-FLIP in multiple human lung cancer cell lines. The presence of the proteasome inhibitor MG132, but not the JNK inhibitor SP600125, prevented CDDO-Me-induced c-FLIP reduction. Moreover, CDDO-Me increased ubiquitination of c-FLIP. Thus, CDDO-Me induces ubiquitin/proteasome-dependent c-FLIP degradation independently of JNK activation. Importantly, overexpression of c-FLIP (e.g., FLIP(L)) protected cells not only from CDDO-Me-induced apoptosis, but also from induction of apoptosis by the combination of CDDO-Me and TRAIL. Accordingly, silencing of c-FLIP with c-FLIP siRNA sensitized cancer cells to CDDO-Me. Collectively, these results indicate that c-FLIP downregulation contributes to CDDO-Me-initiated apoptosis and also to enhancement of TRAIL-induced apoptosis by CDDO-Me.
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PMID:c-FLIP downregulation contributes to apoptosis induction by the novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me) in human lung cancer cells. 1825 90

This study demonstrates that combined treatment with subtoxic doses of quercetin (3',3',4',5,7-pentahydroxyflavone), a flavonoid found in many fruits and vegetables, plus tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rapid apoptosis in TRAIL-resistant hepatocellular carcinoma (HCC) cells. Effective induction of apoptosis by the combined treatment with quercetin and TRAIL was not blocked by overexpression of Bcl-xL, which is known to confer resistance to various chemotherapeutic agents. These results suggest that this combined treatment may provide an attractive strategy for treating resistant HCCs. While the proteolytic processing of procaspase-3 by TRAIL was partially blocked in various HCC cells treated with TRAIL alone, co-treatment with quercetin efficiently recovered TRAIL-induced caspase activation. We found that quercetin treatment of HCC cells significantly up-regulated the mRNA and protein levels of DR5, a death receptor of TRAIL, in a transcription factor Sp1-dependent manner. Furthermore, treatment with quercetin significantly decreased the protein levels of c-FLIP, an inhibitor of caspase-8, through proteasome-mediated degradation. Finally, administration of small interfering RNA against DR5 or overexpression of c-FLIPS, but not c-FLIPL, significantly attenuated quercetin-stimulated TRAIL-induced apoptosis. Collectively, these findings show that quercetin recovers TRAIL sensitivity in various HCC cells via up-regulation of DR5 and down-regulation of c-FLIPS.
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PMID:Quercetin sensitizes human hepatoma cells to TRAIL-induced apoptosis via Sp1-mediated DR5 up-regulation and proteasome-mediated c-FLIPS down-regulation. 1898 Feb 44

Inducing apoptosis via the extrinsic death receptor pathway is an attractive anti-cancer treatment strategy, however, numerous cancer cells exhibit significant resistance to death ligand stimuli. Here, we investigated the anti-neoplastic capability of proteasome inhibition, through the administration of Velcade, to synergize with a death receptor agonist in vivo. The death ligand-resistant LNCaP prostate xenograft model was utilized. Tumors were established and mice were treated with Velcade, TRAIL (TNF-Related Apoptosis Inducing Ligand) or the combined regimen. Only mice treated with a combination of Velcade and TRAIL was tumor growth inhibited with a corresponding loss of the hemorrhagic phenotype, decreased tumor cell proliferation and increased tumor cell apoptosis. Next, to determine if the extrinsic pathway is critical for mediating the anti-tumor efficacy that can be achieved in some cell types with Velcade treatment alone, the death receptor sensitive PC-3 xenograft model was used. PC-3 tumors exhibited a 54% decrease in tumor volume in response to Velcade, while c-FLIP overexpressing PC-3 xenografts were resistant to the treatment. These findings suggest that the extrinsic apoptotic pathway can mediate the anti-tumor effects of Velcade and support the therapeutic use of proteasome inhibition in combination with a death receptor stimulus in the treatment of prostate cancer.
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PMID:Velcade sensitizes prostate cancer cells to TRAIL induced apoptosis and suppresses tumor growth in vivo. 1912 21

The death receptor Fas (APO-1/CD95) induces apoptosis in many tissues upon cross-linking by its ligand (FasL), but a number of cancer cells exhibit resistance to such apoptosis. Indeed, resistance to apoptosis seems to be one of the hallmarks of cancer, and therefore, it is clinically important to understand the underlying mechanisms by which cancer cells acquire such resistance. In the present study, we demonstrate that Fas signaling in DU145 human prostate cancer cells leads to rapid activation of AMP-activated protein kinase (AMPK), which plays a major role in adaptive responses to ATP-depleting conditions; prostate cancer is resistant to Fas-mediated apoptosis despite high levels of Fas surface expression and no mutation in the Fas gene. We further demonstrate that inhibition of AMPK sensitizes DU145 cells to Fas-induced apoptosis via enhancement of ubiquitination and consequent proteasome degradation of the apoptosis inhibitory protein c-FLIP. These findings thus reveal a novel anticancer property of AMPK inhibition and support the synergistic application of AMPK inhibition in cancer therapy to overcome Fas resistance.
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PMID:Down-regulation of AMP-activated protein kinase sensitizes DU145 carcinoma to Fas-induced apoptosis via c-FLIP degradation. 1947 72

In many tumor cell types, ionizing radiation or DNA-damaging anticancer drugs enhance sensitivity to death receptor-mediated apoptosis, which is of clinical interest. APO010, a form of CD95/Fas ligand is currently in a phase I trial in patients with solid tumors. To analyze the potential of combined modality treatment with APO010, we used p53-mutant Jurkat T leukemic cells, in which the mitochondrial pathway was blocked by Bcl-2 overexpression. These cells were strongly sensitized to APO010 by pretreatment with ionizing - or UV radiation, etoposide, histone deacetylase - or proteasome inhibitors. These stimuli alone did not induce apoptosis in J16-Bcl-2 cells. Sensitization could not be explained by the overruling of mitochondrial resistance imposed by Bcl-2, upregulation of CD95 membrane levels or modulation of inhibitor of apoptosis proteins. Rather, the stimuli commonly downregulated c-FLIP(L/S) protein levels, which was causally related to the sensitization: deliberate c-FLIP(L/S) downregulation by RNA interference largely overruled the capacity of the various stimuli to sensitize Jurkat-Bcl-2 cells to apoptotic execution by APO010. In p53-mutant, Bcl-2 overexpressing HCT-15 colon carcinoma cells, c-FLIP downregulation correlated with sensitization to APO010 for some, but not all stimuli. We conclude that c-FLIP downregulation represents a mechanism by which diverse anticancer regimens can facilitate tumor cell execution by CD95/Fas through the direct pathway of caspase activation.
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PMID:Radiation and anticancer drugs can facilitate mitochondrial bypass by CD95/Fas via c-FLIP downregulation. 1979 6

The ALP (alkyl-lysophospholipid) edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) induces apoptosis in S49 mouse lymphoma cells. A variant cell line, S49AR, made resistant to ALP, was found previously to be impaired in ALP uptake via lipid-raft-mediated endocytosis. In the present paper, we report that these cells display cross-resistance to Fas/CD95 ligation [FasL (Fas ligand)], and can be gradually resensitized by prolonged culturing in the absence of ALP. Fas and ALP activate distinct apoptotic pathways, since ALP-induced apoptosis was not abrogated by dominant-negative FADD (Fas-associated protein with death domain), cFLIP(L) [cellular FLICE (FADD-like interleukin 1beta-converting enzyme)-inhibitory protein long form] or the caspase 8 inhibitor Z-IETD-FMK (benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethylketone). ALP-resistant cells showed decreased Fas expression, at both the mRNA and protein levels, in a proteasome-dependent fashion. The proteasome inhibitor MG132 partially restored Fas expression and resensitized the cells to FasL, but not to ALP. Resistant cells completely lacked SM (sphingomyelin) synthesis, which seems to be a unique feature of the S49 cell system, having very low SM levels in parental cells. Lack of SM synthesis did not affect cell growth in serum-containing medium, but retarded growth under serum-free (SM-free) conditions. SM deficiency determined in part the resistance to ALP and FasL. Exogenous short-chain (C12-) SM partially restored cell-surface expression of Fas in lipid rafts and FasL sensitivity, but did not affect Fas mRNA levels or ALP sensitivity. We conclude that the acquired resistance of S49 cells to ALP is associated with down-regulated SM synthesis and Fas gene transcription and that SM in lipid rafts stabilizes Fas expression at the cell surface.
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PMID:Fas/CD95 down-regulation in lymphoma cells through acquired alkyllysophospholipid resistance: partial role of associated sphingomyelin deficiency. 1982 85

Verotoxin (VT-1) is a cytotoxin, produced by Shigella dysenteriae type 1 or by Shiga toxin-producing Escherichia coli, which binds specifically to globotriaosylceramide (Gb3). This glycosphingolipid is a B cell differentiation antigen (Gb3/CD77) strongly expressed on Burkitt's lymphoma cells. We have previously shown that, in these cells, VT-1 induces apoptosis via a caspase- and mitochondria-dependent pathway. In this report, we provide new insights into this signal transduction pathway. First, we demonstrate that VT-1-induced apoptosis requires degradation of the caspase-8 inhibitory molecule c-FLIPL and that this degradation occurs through the ubiquitin-proteasome pathway. Furthermore, we show that mitochondrial activation is mainly due to i) cleavage and activation of the pro-apoptotic Bcl-2 family member Bid by caspase-8 and ii) Bax relocalization to mitochondrial membranes which lead to cytochrome c release. However, tBid is not involved in Bax relocalization, and relocalization is most likely controlled by the extent of Bax phosphorylation: in non-treated BL cells, p38 MAPK participates in the retention of Bax in the cytoplasm in an inactive form whereas in VT-1 treated cells, protein phosphatase 2A is activated and induces Bax relocalization to mitochondria.
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PMID:Caspase-8-mediated cleavage of Bid and protein phosphatase 2A-mediated activation of Bax are necessary for Verotoxin-1-induced apoptosis in Burkitt's lymphoma cells. 1989 84

Thiazolidinediones, including rosiglitazone and troglitazone, are insulin-sensitizing drugs and high-affinity ligands for the peroxisome proliferator-activated receptor gamma (PPARgamma). Apart from their antidiabetic activity, these molecules possess antitumor properties. We investigated their potential apoptotic effects on RT4 (derived from a well-differentiated Grade I papillary tumor) and T24 (derived from an undifferentiated Grade III carcinoma) bladder cancer cells. Rosiglitazone induced G2/M or G0/G1 phase cell cycle arrest in RT4 and T24 cells, respectively. Only troglitazone triggered apoptosis via extrinsic and intrinsic pathways in both cell lines. Interestingly, rosiglitazone amplified TRAIL-induced apoptosis in TRAIL-sensitive RT4 cells or let TRAIL-resistant T24 cells to respond to TRAIL. Thiazolidinediones acted through PPARgamma activation-independent mechanisms. The underlying mechanisms involved for the first time in cancer cells the upregulation of soluble and/or membrane-bound TRAIL. This was associated with increased cell surface death receptor 5 expression and c-FLIP and survivin downregulation, mediated in part through proteasome-dependent degradation in troglitazone-promoted cell death. Therefore, the combination of rosiglitazone and TRAIL could be clinically relevant as chemopreventive or therapeutic agents for the treatment of TRAIL-resistant high-grade urothelial cancers.
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PMID:Insights on distinct pathways of thiazolidinediones (PPARgamma ligand)-promoted apoptosis in TRAIL-sensitive or -resistant malignant urothelial cells. 2009 77


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