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)

Solid tumors commonly contain regions with glucose-starved and hypoxic conditions. Tumor cells under the adverse conditions can survive through the stress response, such as cell cycle arrest. In this study, we found that the stress conditions stimulated nuclear accumulation of proteasomes, large multicatalytic protease complexes, in human colon cancer HT-29 cells. The nuclear proteasome levels both in amount and in activity were increased approximately 4 and 2 times by glucose starvation and hypoxia, respectively. No changes were detected in the total expression levels of proteasome. The nuclear proteasome accumulation was also observed in ovarian cancer A2780 cells under glucose starvation, suggesting that this response was regardless of the origin of cancer cells. Our results indicate that the nuclear proteasome distribution is enhanced by glucose starvation and hypoxia, and suggest that the proteolysis by proteasome in the nucleus may play roles in the stress response of solid tumor cells.
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PMID:Glucose starvation and hypoxia induce nuclear accumulation of proteasome in cancer cells. 1032 7

Angiogenesis is a prerequisite for solid tumor growth and metastasis. Elucidation of the signaling pathways that control tumor angiogenesis constitutes the basis for a rational antiangiogenic tumor therapy. Here we show that the production of vascular endothelial growth factor (VEGF) in HeLa and HL-60 cells is directed by the constitutive photomorphogenesis 9 signalosome (CSN). The CSN is a kinase complex that cooperates with the ubiquitin/26S proteasome system in regulating the stability of proteins involved in signal transduction. VEGF expression is controlled by the transcription factors activator protein (AP)-1, AP-2, SP-1, and hypoxia-inducible factor 1. Inhibition of CSN kinase activity by 50 microM curcumin for 2 h decreases the cellular c-Jun concentration, resulting in a reduction of the VEGF production by approximately 75%. The removal of the inhibitor from the cells led to a time-dependent recovery of endogenous c-Jun that is paralleled by increasing VEGF production. Elevated cellular CSN activity induced by CSN subunit 2 overexpression causes increased VEGF production in HeLa cells. A competitor of CSN-dependent c-Jun phosphorylation, the NH(2)-terminal c-Jun fragment Deltac-Jun(1-226), inhibits VEGF production in HeLa cells. The transcription factors AP-2 and SP-1 act independently of the CSN. They contribute less than a quarter to basal VEGF production. Under our experimental conditions, hypoxia-inducible factor 1alpha protein was not detected. Overexpression of the tumor suppressor p53 reduces VEGF production in HeLa cells. p53 competes with c-Jun for CSN-specific phosphorylation with the consequence of c-Jun destabilization. We conclude that CSN-directed c-Jun signaling mediates high VEGF production in HeLa and HL-60 cells. The data provide an explanation for the known antiangiogenic and antitumorigenic activities of curcumin. Because the CSN regulates the major part of VEGF production in the tested tumor cells, it constitutes a potentially important target for tumor therapy.
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PMID:The constitutive photomorphogenesis 9 signalosome directs vascular endothelial growth factor production in tumor cells. 1173 21

Over the last decade, the critical role of the proteasome in cell-cycle regulation has become increasingly apparent. The proteasome, a multicatalytic protease present in all eukaryotic cells, is the primary component of the protein degradation pathway of the cell. By degrading regulatory proteins (or their inhibitors), the proteasome serves as a central conduit for many cellular regulatory signals and, thus, is a novel target for therapeutic drugs. PS-341 is a small molecule that is a potent and selective inhibitor of the proteasome. In vitro and mouse xenograft studies of PS-341 have shown antitumor activity in a variety of tumor types, including myeloma, chronic lymphocytic leukemia, prostate cancer, pancreatic cancer, and colon cancer, among others. Although PS-341 rapidly leaves the vascular compartment, a novel pharmacodynamic assay has shown that inhibition of proteasome-the biologic target-is dose dependent and reversible. These studies provided the rationale for a twice-weekly dosing schedule employed in ongoing clinical studies. Phase I trials in a variety of tumor types have shown PS-341 to be well tolerated, and phase II trials in several hematologic malignancies and solid tumor types are now in progress. Efficacy and safety data from the most advanced of these, a phase II multicenter trial in myeloma, will be available in early 2002.
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PMID:Development of the proteasome inhibitor PS-341. 1185 43

The central role of the proteasome in controlling the expression of regulators of cell proliferation and survival has led to interest in developing proteasome inhibitors as novel anticancer agents. In vitro and in vivo studies have shown that proteasome inhibitors have activity against a variety of tumor types. One of these agents, PS-341, has been tested in phase I trials in a variety of tumor types; in these trials, PS-341 treatment was well tolerated and preliminary evidence of biological activity was observed in some patients. Phase II trials in several hematological malignancies and solid tumor types are now in progress.
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PMID:Proteasome inhibition: a novel approach to cancer therapy. 1192 88

The ubiquitin-proteasome pathway has a central role in the selective degradation of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. Consequently proteasome inhibition is a potential treatment option for cancer and inflammatory conditions. Thus far, proof of principle has been obtained from studies in numerous animal models for a variety of human diseases including cancer, reperfusion injury, and inflammatory conditions such as rheumatoid arthritis, asthma, multiple sclerosis, and psoriasis. Two proteasome inhibitors, each representing a unique chemical class, are currently under clinical evaluation. Velcade (PS-341) is currently being evaluated in multiple phase II clinical trials for several solid tumor indications and has just entered a phase III trial for multiple myeloma. PS-519, representing another class of inhibitors, focuses on the inflammatory events following ischemia and reperfusion injury. Since proteasome inhibitors exhibit anti-inflammatory and antiproliferative effects, diseases characterized by both of these processes simultaneously, as is the case in rheumatoid arthritis or psoriasis, might also represent clinical opportunities for such drugs.
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PMID:Proteasome inhibition: a new anti-inflammatory strategy. 1270 Aug 91

Given its role in cellular metabolism, the proteasome could prove to be a critical target that can be exploited in treating cancer. In preclinical studies, several mechanisms for bortezomib's activity in multiple myeloma cells have been identified (e.g., NF-kappaB inhibition); antitumor activity with bortezomib has been seen in myeloma patients, thereby supporting the validity of the preclinical work. Similar mechanisms may be in play in solid tumors, and cell culture and xenograft data suggest bortezomib may be active in a wide range of tumor types. One promising possibility is the use of bortezomib for the treatment of chemoresistant tumors. Chemoresistance can be caused by a number of cellular factors; NF-kappaB is a prominent instigator of chemoresistance, and proteasome inhibition was an effective means of preventing NF-kappaB activation in myeloma and several solid tumor laboratory studies. However, the inhibition of NF-kappaB may not be the only mechanism for antitumor activity. This review explores the use of proteasome inhibitors to subvert intrinsic resistance mechanisms, disrupt inducible chemoresistance, or augment the mechanisms of action of standard chemotherapeutics. Thus, in addition to providing another target for anticancer treatment, proteasome inhibition may also provide a means to treat refractory tumors.
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PMID:Rationale for the treatment of solid tumors with the proteasome inhibitor bortezomib. 1273 40

Epidemiological studies have suggested that increased soy consumption is associated with reduced cancer occurrence. Genistein, a soy isoflavone, has been reported to inhibit the growth of human tumor cells although the involved molecular mechanisms are not clearly defined. Here we report that genistein inhibits the proteasomal chymotrypsin-like activity in vitro and in vivo. Computational docking studies suggest that the interaction of genistein with the proteasomal beta 5 subunit is responsible for inhibition of the chymotrypsin-like activity. Inhibition of the proteasome by genistein in prostate cancer LNCaP and breast cancer MCF-7 cells is associated with accumulation of ubiquitinated proteins and three known proteasome target proteins, the cyclin-dependent kinase inhibitor p27(Kip1), inhibitor of nuclear factor-kappa B (I kappa B-alpha), and the pro-apoptotic protein Bax. Genistein-mediated proteasome inhibition was accompanied by induction of apoptosis in these solid tumor cells. Finally, genistein induced proteasome inhibition and apoptosis selectively in simian virus 40-transformed human fibroblasts, but not in their parental normal counterpart. Our results suggest that the proteasome is a potential target of genistein in human tumor cells and that inhibition of the proteasome activity by genistein might contribute to its cancer-preventive properties.
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PMID:Inhibition of the proteasome activity, a novel mechanism associated with the tumor cell apoptosis-inducing ability of genistein. 1296 83

Androgen ablation and chemotherapy provide effective palliation for most patients with advanced prostate cancer, but eventually progressing androgen-independent prostate cancer threatens the lives of patients usually within a few years, mandating improvement in therapy. Proteasome inhibition has been proposed as a therapy target for the treatment of solid and hematological malignancies. The proteasome is a ubiquitous enzyme complex that is a hub for the regulation of many intracellular regulatory pathways; because of its essential function, this enzyme has become a new target for cancer treatment. Studies with bortezomib (VELCADE, formerly known as PS-341) and other proteasome inhibitors indicate that cancer cells are especially dependent on the proteasome for survival, and several mechanisms used by prostate cancer cells require proteasome function. Bortezomib has been studied extensively in vitro and in vivo, and anticancer activity has been seen in cell and animal models for several solid tumor types, including prostate cancer. A Phase I trial to determine the maximum tolerated dose of once-weekly bortezomib has been completed. This trial included a large fraction of patients with androgen-independent prostate cancer. The maximum tolerated dose was reached at 1.6 mg/m(2). A correlation was seen among bortezomib dose, proteasome inhibition, and positive modulation of serum prostate-specific antigen. There was also evidence of down-regulation of serum interleukin 6, a downstream nuclear factor kappaB effector. This Phase I trial and preclinical studies support additional testing of bortezomib in combination with radiation or chemotherapy for androgen-independent prostate cancer.
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PMID:Bortezomib as a potential treatment for prostate cancer. 1528 99

Cancer cachexia is a serious and life-treating syndrome that appears in most solid tumor patients. The syndrome is associated with anorexia, loss of protein mass, wasting of lipids, and disturbances of carbohydrate metabolism. Moreover, psychological distress and lower quality of life are often seen in patients with cancer cachexia. The latter is a multimodality process in which cytokine interactions, action of enzymes playing a key role in lipid metabolism, and activity of proteolytic proteinases are the complex net that are responsible for destruction of an organism suffering from cancer cachexia. Recently, it has been shown a growing role of ubiquitin-proteasome pathway in cachexia. Biochemical interactions are crucial for further study, mainly, when a novel target therapy appears to treat cancer in different modalities. In case of proteasome, PS-341 (bortezomib, Velcade) an inhibitor of proteasome is under investigation in clinical trials phase I.
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PMID:[The role of proteasome in pathophysiology of cancer cachexia]. 1560 47

The proteasome is the main extralysosomal system involved in intracellular proteolysis. A number of proteasome substrates, including cyclins, IkappaB, and p53, are critical to cell cycle progression and apoptosis. Interruption of the degradation of these substrates through proteasome inhibition is a novel and unique approach to the treatment of malignancies. First-generation proteasome inhibitors lacked usefulness because of broad specificity and irreversible binding to the proteasome. However, the later synthesis of the peptide boronic acid proteasome inhibitor bortezomib allowed for selective, reversible binding. Basic investigations have reported the antitumor activity of bortezomib in a variety of hematologic and solid tumor models and have demonstrated the ability of bortezomib to enhance chemosensitivity and overcome cellular mechanisms of drug resistance attributable, in part, to abrogation of NF-kappaB induction. In patients with relapsed, refractory multiple myeloma who had received a median of six prior regimens, treatment with bortezomib resulted in a 35% response rate (complete plus partial plus minimal response) using criteria of the European Group for Blood and Marrow Transplantation. Encouraging activity has been demonstrated with bortezomib in the first-line treatment of myeloma and in patients with mantle cell lymphoma. Investigations of its utility in the treatment of patients with solid tumors are ongoing.
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PMID:Proteasome inhibition in the treatment of cancer. 1565 70


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