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)

Androgen receptor plays a critical role in the development of primary as well as advanced hormone-refractory prostate cancer. Therefore, ablation of androgen receptor from prostate cancer cells is an interesting concept for developing a new therapy not only for androgen-dependent prostate cancer but also for metastatic hormone-refractory prostate cancer, for which there is no effective treatment available. We report here that LAQ824, a cinnamyl hydroxamatic acid histone deacetylase inhibitor currently in human clinical trials, effectively depleted androgen receptor in prostate cancer cells at nanomolar concentrations. LAQ824 seemed capable of depleting both the mutant and wild-type androgen receptors in either androgen-dependent and androgen-independent prostate cancer cells. Although LAQ824 may exert its effect through multiple mechanisms, several lines of evidence suggest that inactivation of the heat shock protein-90 (Hsp90) molecular chaperone is involved in LAQ824-induced androgen receptor depletion. Besides androgen receptor, LAQ824 reduced the level of Hsp90 client proteins HER-2 (ErbB2), Akt/PKB, and Raf-1 in LNCaP cells. Another Hsp90 inhibitor, 17-allyamino-17-demethoxygeldanamycin (17-AAG), also induced androgen receptor diminution. LAQ824 induced Hsp90 acetylation in LNCaP cells, which resulted in inhibition of its ATP-binding activity, dissociation of Hsp90-androgen receptor complex, and proteasome-mediated degradation of androgen receptor. Consequently, LAQ824 blocked androgen-induced prostate-specific antigen production in LNCaP cells. LAQ824 effectively inhibited cell proliferation and induced apoptosis of these prostate cancer cells. These results reveal that LAQ824 is a potent agent for depletion of androgen receptor and a potential new drug for prostate cancer.
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PMID:Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824. 1617 22

The role of the ubiquitin/proteasome system in degrading nuclear hormone receptors and regulating their transcriptional function has emerged in the last few years. We identified the ubiquitin-specific protease USP10 as part of DNA-bound androgen receptor (AR) complexes purified from nuclear extracts of PC-3 cells stably expressing the AR. The interaction between USP10 and the AR was confirmed by GST pull-down assays. Fluorescence microscopy documented that USP10 was localised in the nucleus and the cytoplasm. Cell-based transactivation assays in PC-3/AR cells revealed that overexpression of wild-type USP10, but not of an enzymatically inactive form, stimulated AR activity mediated by reporter constructs harbouring selective androgen response elements (AREs), non-selective steroid response elements (SREs) or the mouse mammary tumour virus (MMTV) promoter. Conversely, USP10 expression knock-down by siRNAs impaired the MMTV response to androgen. In summary, the data indicate that USP10 is a new cofactor that binds to the AR and stimulates the androgen response of target promoters. This finding underlines the role of the ubiquitin/proteasome system in modulating the AR function.
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PMID:The ubiquitin-specific protease USP10 modulates androgen receptor function. 1636 82

Capsaicin is the major pungent ingredient in red peppers. Here, we report that it has a profound antiproliferative effect on prostate cancer cells, inducing the apoptosis of both androgen receptor (AR)-positive (LNCaP) and -negative (PC-3, DU-145) prostate cancer cell lines associated with an increase of p53, p21, and Bax. Capsaicin down-regulated the expression of not only prostate-specific antigen (PSA) but also AR. Promoter assays showed that capsaicin inhibited the ability of dihydrotestosterone to activate the PSA promoter/enhancer even in the presence of exogenous AR in LNCaP cells, suggesting that capsaicin inhibited the transcription of PSA not only via down-regulation of expression of AR, but also by a direct inhibitory effect on PSA transcription. Capsaicin inhibited NF-kappa activation by preventing its nuclear migration. In further studies, capsaicin inhibited tumor necrosis factor-alpha-stimulated degradation of IkappaBalpha in PC-3 cells, which was associated with the inhibition of proteasome activity. Taken together, capsaicin inhibits proteasome activity which suppressed the degradation of IkappaBalpha, preventing the activation of NF-kappaB. Capsaicin, when given orally, significantly slowed the growth of PC-3 prostate cancer xenografts as measured by size [75 +/- 35 versus 336 +/- 123 mm(3) (+/-SD); P = 0.017] and weight [203 +/- 41 versus 373 +/- 52 mg (+/-SD); P = 0.0006; capsaicin-treated versus vehicle-treated mice, respectively]. In summary, our data suggests that capsaicin, or a related analogue, may have a role in the management of prostate cancer.
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PMID:Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells. 1654 Jun 74

Prostate cancer cells rely on androgen receptor (AR) for proliferation and survival. Therefore, curing prostate cancer will require elimination of AR. Although androgen is the natural ligand that activates AR, AR activity is also subject to regulation by growth factor/growth factor receptor-stimulated signaling pathways that control the cell cycle. Cell cycle regulatory proteins and protein kinases in signaling pathways affected by growth factors can lead to AR activation in the absence of androgen. While downstream signaling proteins such as cyclins, cyclin-dependent kinases (CDKs), and pRB can modulate AR activity, upstream signaling pathways involving protein kinases such as mitogen-activated protein kinases, protein kinase A, and protein kinase B/Akt can affect post-translational modification of AR to affect not only AR function but also AR stability. Calcium and calmodulin (CaM), essential for proliferation and viability of a number of cells, including prostate cancer cells, play an important role in AR expression, stability, and function. CaM affects AR partly by interacting directly with AR and partly by activating protein kinases such as Akt and DNA-PK that can phosphorylate AR. The ubiquitin/26S proteasome pathway responsible for timely destruction of cell cycle regulatory proteins whose levels impede cell cycle progression also induces AR expression by activating NF-kappaB, and promotes AR activity by participating in the assembly of an AR transcription complex. Maspin, a serine protease inhibitor that is known mostly for its role as a tumor suppressor can also regulate AR intracellular localization and function by competing with AR for binding to the chaperone protein Hsp90 and co-repressor HDAC1, respectively. This perspective reviews the experimental evidence implicating these diverse cellular processes in AR expression, stability, and/or function, and presents a rationale for disrupting these cellular processes as a viable option for the treatment of both the hormone-sensitive and the hormone-insensitive prostate cancer.
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PMID:Regulatory processes affecting androgen receptor expression, stability, and function: potential targets to treat hormone-refractory prostate cancer. 1661 63

Interest in the use of traditional medicines for cancer prevention and treatment is increasing. In vitro, in vivo, and clinical studies suggest the potential use of proteasome inhibitors as novel anticancer drugs. Celastrol, an active compound extracted from the root bark of the Chinese medicine "Thunder of God Vine" (Tripterygium wilfordii Hook F.), was used for years as a natural remedy for inflammatory conditions. Although Celastrol has been shown to induce leukemia cell apoptosis, the molecular target involved has not been identified. Furthermore, whether Celastrol has antitumor activity in vivo has never been conclusively shown. Here, we report, for the first time, that Celastrol potently and preferentially inhibits the chymotrypsin-like activity of a purified 20S proteasome (IC(50) = 2.5 micromol/L) and human prostate cancer cellular 26S proteasome (at 1-5 micromol/L). Inhibition of the proteasome activity by Celastrol in PC-3 (androgen receptor- or AR-negative) or LNCaP (AR-positive) cells results in the accumulation of ubiquitinated proteins and three natural proteasome substrates (IkappaB-alpha, Bax, and p27), accompanied by suppression of AR protein expression (in LNCaP cells) and induction of apoptosis. Treatment of PC-3 tumor-bearing nude mice with Celastrol (1-3 mg/kg/d, i.p., 1-31 days) resulted in significant inhibition (65-93%) of the tumor growth. Multiple assays using the animal tumor tissue samples from both early and end time points showed in vivo inhibition of the proteasomal activity and induction of apoptosis after Celastrol treatment. Our results show that Celastrol is a natural proteasome inhibitor that has a great potential for cancer prevention and treatment.
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PMID:Celastrol, a triterpene extracted from the Chinese "Thunder of God Vine," is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. 1665 29

In Eukarya, the 26S proteasome is primarily responsible for intracellular protein degradation. To be degraded, proteins must be ubiquitinated. The latter requires a multi-enzyme cascade consisting of an E1, an E2, and an E3 enzyme. While there is only a single E1 and a few E2s, there are many different E3s that target substrates by recognizing specific sequence motifs, known as degrons. Here, we have used the peptide array technology to identify binding motifs in the human androgen receptor (AR), which are recognized by the Carboxyl-terminus of Hsc70-Interacting Protein (CHIP), a U-box E3 and Hsp70/Hsp90 co-chaperone. We show that CHIP recognizes AR in a highly specific, phosphorylation- and sequence-dependent manner, and propose that this interaction could provide a mechanism that regulates the degradation of CHIP substrates.
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PMID:The E3 ubiquitin ligase CHIP binds the androgen receptor in a phosphorylation-dependent manner. 1672 94

Abnormal accumulation of disease-causing protein is a commonly observed characteristic in chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and polyglutamine (polyQ) diseases. A therapeutic approach that could selectively eliminate would be a promising remedy for neurodegenerative disorders. Spinal and bulbar muscular atrophy (SBMA), one of the polyQ diseases, is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. The pathogenic gene product is polyQ-expanded androgen receptor (AR), which belongs to the heat shock protein (Hsp) 90 client protein family. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a novel Hsp90 inhibitor, is a new derivative of geldanamycin that shares its important biological activities but shows less toxicity. 17-AAG is now in phase II clinical trials as a potential anti-cancer agent because of its ability to selectively degrade several oncoproteins. We have recently demonstrated the efficacy and safety of 17-AAG in a mouse model of SBMA. The administration of 17-AAG significantly ameliorated polyQ-mediated motor neuron degeneration by reducing the total amount of mutant AR. 17-AAG accomplished the preferential reduction of mutant AR mainly through Hsp90 chaperone complex formation and subsequent proteasome-dependent degradation. 17-AAG induced Hsp70 and Hsp40 in vivo as previously reported; however, its ability to induce HSPs was limited, suggesting that the HSP induction might support the degradation of mutant protein. The ability of 17-AAG to preferentially degrade mutant protein would be directly applicable to SBMA and other neurodegenerative diseases in which the disease-causing proteins also belong to the Hsp90 client protein family. Our proposed therapeutic approach, modulation of Hsp90 function by 17-AAG treatment, has emerged as a candidate for molecular-targeted therapies for neurodegenerative diseases. This review will consider our research findings and discuss the possibility of a clinical application of 17-AAG to SBMA and other neurodegenerative diseases.
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PMID:Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein. 1674 51

Aggregates, a hallmark of most neurodegenerative diseases, may have different properties, and possibly different roles in neurodegeneration. We analysed ubiquitin-proteasome pathway functions during cytoplasmic aggregation in polyglutamine (polyQ) diseases, using a unique model of motor neuron disease, the SpinoBulbar Muscular Atrophy. The disease, which is linked to a polyQ tract elongation in the androgen receptor (ARpolyQ), has the interesting feature that ARpolyQ aggregation is triggered by the AR ligand, testosterone. Using immortalized motor neurons expressing ARpolyQ, we found that a proteasome reporter, YFPu, accumulated in absence of aggregates; testosterone treatment, which induced ARpolyQ aggregation, allowed the normal clearance of YFPu, suggesting that aggregation contributed to proteasome de-saturation, an effect not related to AR nuclear translocation. Using AR antagonists to modulate the kinetic of ARpolyQ aggregation, we demonstrated that aggregation, by removing the neurotoxic protein from the soluble compartment, protected the proteasome from an excess of misfolded protein to be processed.
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PMID:Aggregation and proteasome: the case of elongated polyglutamine aggregation in spinal and bulbar muscular atrophy. 1678 Oct 19

The 20 S proteasome is a ubiquitous, barrel-shaped protease complex responsible for most of cellular proteolysis, and its reduced activity is thought to be associated with accumulations of aberrant or misfolded proteins, resulting in a number of neurodegenerative diseases, including amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, Parkinson disease, and Alzheimer disease. The 20 S proteasomes of archaebacteria (archaea) are structurally simple and proteolytically powerful and thought to be an evolutionary precursor to eukaryotic proteasomes. We successfully reproduced the archaeal proteasome in a functional state in mammalian cells, and here we show that the archaeal proteasome effectively accelerated species-specific degradation of mutant superoxide dismutase-1 and the mutant polyglutamine tract-extended androgen receptor, causative proteins of familial amyotrophic lateral sclerosis and spinal and bulbar muscular atrophy, respectively, and reduced the cellular toxicities of these mutant proteins. Further, we demonstrate that archaeal proteasome can also degrade other neurodegenerative disease-associated proteins such as alpha-synuclein and tau. Our study showed that archaeal proteasomes can degrade aggregation-prone proteins whose toxic gain of function causes neurodegradation and reduce protein cellular toxicity.
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PMID:Archaeal proteasomes effectively degrade aggregation-prone proteins and reduce cellular toxicities in mammalian cells. 1679 67

The androgen receptor (AR) is a transcription factor belonging to the family of nuclear receptors which mediates the action of androgens in the development of urogenital structures. AR expression is regulated post-translationally by the ubiquitin/proteasome system. This regulation involves more complex mechanisms than typical degradation. The ubiquitin/proteasome system may regulate AR via mechanisms that do not engage in receptor turnover. Given the critical role of AR in sexual development, this complex regulation is especially important. Deregulation of AR signalling may be a causal factor in prostate cancer development. AR is the main target in prostate cancer therapies. Due to the critical role of the ubiquitin/proteasome system in AR regulation, current research suggests that targeting AR degradation is a promising approach.
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PMID:Degradation and beyond: control of androgen receptor activity by the proteasome system. 1684 54


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