Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our previous studies showed that BikDD, a constitutively active mutant form of Bik, exhibited powerful antitumor effects in preclinical pancreatic, lung and breast cancer models. Howerver, the antitumor activity of BikDD in triple-negative breast cancer (TNBC) is unknown. Here we show that aberrant expression of p-ERK1/2 was a meaningful molecular phenotype in TNBC patients, and can be an obstacle for treatment because of the converse correlation with Bik. A novel mutant, BikDDA, in which Ser124 was changed to Alanine to block BikDD phosphorylation by p-ERK1/2 prevented subsequent ubiquitin-proteasome degradation. BikDDA showed a prolonged half-life and enhanced pro-apoptotic ability in TNBC cells compared with BikDD. Moreover, aberrant expression of p-ERK1/2 was associated with 5-fluorouracil resistance in breast cancer patients and BikDDA enhanced the therapeutic effects of 5-fluorouracil in vitro.
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PMID:BikDDA, a mutant of Bik with longer half-life expression protein, can be a novel therapeutic gene for triple-negative breast cancer. 2463 19

Acquired resistance to proteasome inhibitors represents a considerable impediment to their effective clinical application. Carfilzomib and its orally bioavailable structural analog oprozomib are second-generation, highly-selective, proteasome inhibitors. However, the mechanisms of acquired resistance to carfilzomib and oprozomib are incompletely understood, and effective strategies for overcoming this resistance are needed. Here, we developed models of acquired resistance to carfilzomib in two head and neck squamous cell carcinoma cell lines, UMSCC-1 and Cal33, through gradual exposure to increasing drug concentrations. The resistant lines R-UMSCC-1 and R-Cal33 demonstrated 205- and 64-fold resistance, respectively, relative to the parental lines. Similarly, a high level of cross-resistance to oprozomib, as well as paclitaxel, was observed, whereas only moderate resistance to bortezomib (8- to 29-fold), and low level resistance to cisplatin (1.5- to 5-fold) was seen. Synergistic induction of apoptosis signaling and cell death, and inhibition of colony formation followed co-treatment of acquired resistance models with carfilzomib and the histone deacetylase inhibitor (HDACi) vorinostat. Synergism was also seen with other combinations, including oprozomib plus vorinostat, or carfilzomib plus the HDACi entinostat. Synergism was accompanied by upregulation of proapoptotic Bik, and suppression of Bik attenuated the synergy. The acquired resistance models also exhibited elevated levels of MDR-1/P-gp. Inhibition of MDR-1/P-gp with reversin 121 partially overcame carfilzomib resistance in R-UMSCC-1 and R-Cal33 cells. Collectively, these studies indicate that combining carfilzomib or oprozomib with HDAC or MDR-1/P-gp inhibitors may be a useful strategy for overcoming acquired resistance to these proteasome inhibitors.
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PMID:Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors. 2491 39

Intrinsic apoptosis involves BH3-only protein activation of Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP). Consequently, cytochrome c is released from the mitochondria to activate caspases, and Smac (second mitochondria-derived activator of caspases) to inhibit XIAP-mediated caspase suppression. Dysfunctional mitochondria can be targeted for lysosomal degradation via autophagy (mitophagy), or directly through mitochondria-derived vesicle transport. However, the extent of autophagy and lysosomal interactions with apoptotic mitochondria remains largely unknown. We describe here a novel pathway of endolysosomal processing of mitochondria, activated in response to canonical BH3-only proteins and mitochondrial depolarization. We report that expression of canonical BH3-only proteins, tBid, BimEL, Bik, Bad, and mitophagy receptor mutants of atypical BH3-only proteins, Bnip3 and Bnip3L/Nix, leads to prominent relocalization of endolysosomes into inner mitochondrial compartments, in a manner independent of mitophagy. As an upstream regulator, we identified the XIAP E3 ligase. In response to mitochondrial depolarization, XIAP actuates Bax-mediated MOMP, even in the absence of BH3-only protein signaling. Subsequently, in an E3 ligase-dependent manner, XIAP rapidly localizes inside all the mitochondria, and XIAP-mediated mitochondrial ubiquitylation catalyses interactions of Rab membrane targeting components Rabex-5 and Rep-1 (RFP-tagged Rab escort protein-1), and Rab5- and Rab7-positive endolysosomes, at and within mitochondrial membrane compartments. While XIAP-mediated MOMP permits delayed cytochrome c release, within the mitochondria XIAP selectively signals lysosome- and proteasome-associated degradation of its inhibitor Smac. These findings suggest a general mechanism to lower the mitochondrial apoptotic potential via intramitochondrial degradation of Smac.
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PMID:Intramitochondrial recruitment of endolysosomes mediates Smac degradation and constitutes a novel intrinsic apoptosis antagonizing function of XIAP E3 ligase. 2508 Sep 38

BikDD, a phosphorylation-mimic mutant of pro-apoptotic protein Bik, elicits strong apoptosis in cancer cells when introduced via an expression platform termed VP16-GAL4-WPRE integrated systemic amplifier (VISA) under the control of a cancer-specific promoter both in vitro and in vivo. C-VISA-BikDD expression plasmid encapsulated in liposomes is currently in the process to initiate a phase I clinical trial for pancreatic cancer. In this study, we report a potential combination approach of BikDD with proteasome inhibitors on the basis of our findings that exogenously expressed BikDD protein undergoes proteasome-mediated degradation via both ubiquitin-dependent and -independent pathways. Inhibition of proteasome increases the protein stability of BikDD, enhancing the apoptotic effect of BikDD. Hence, high proteasome activity may be a mechanism by which intrinsic and acquired resistance occurs in BikDD gene therapy, and a combination therapy with current clinically approved proteasome inhibitor may overcome resistance.
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PMID:Proteasome inhibition enhances the killing effect of BikDD gene therapy. 2590 Dec

The proteasome inhibitor bortezomib is a promising novel agent in bladder cancer therapy; however, inducible cytoprotective mechanisms may limit its potential efficacy. To date, the cellular and molecular effects of proteasome inhibitors on bladder cancer cells have been poorly characterized. Despite the consistent rate of initial responses, cisplatin treatment typically results in the development of chemoresistance, leading to therapeutic failure. Therefore, the present study aimed to characterize the molecular mechanisms underlying the anti-proliferative effects of cisplatin and bortezomib combination therapy on the human T24 bladder cancer cell line, by analyzing the protein expression levels of apoptotic genes. Cytotoxic effects were measured using a water-soluble tetrazolium salt-1 assay, and the apoptosis-associated molecules were examined using western blot analysis and ELISA. It was observed that combined administration of cisplatin and bortezomib induced upregulation of caspase-3, -8 and -9, B-cell lymphoma-2 (Bcl-2)-like 11 and Bcl-2-interacting killer, but downregulated Bcl-2 and Bcl-extra large protein expression levels in T24 cells in a dose-dependent manner. Furthermore, enhanced protein expression of caspase-8 and -9, in line with the significantly increased caspase-3 activation, was detected when the cells were treated with a combination of cisplatin and bortezomib, compared with that of either agent alone. Bortezomib appeared to synergize with cisplatin to promote apoptosis via the extrinsic and intrinsic apoptotic pathways. Taken together, the results of the current study provide the preclinical framework for additional evaluation of the effects of combining bortezomib with other agents to induce apoptosis in bladder cancer cells.
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PMID:Synergistic effects of cisplatin and proteasome inhibitor bortezomib on human bladder cancer cells. 2617 Oct 69

Cerebral ischemia is accompanied by mitochondrial integrity destruction. Thus, reversion of mitochondrial damage holds great potential for cerebral ischemia therapy. As a crucial Bcl-2 family member, pro-apoptotic Bax protein is a main effector of mitochondrial permeabilization and plays an important role in mitochondrial homeostasis. However, there is still a lack of an effective cerebral protective strategy through selectively targeting Bax. In this study, we reported that natural small-molecule protosappanin A (PTA) showed a significant mitochondrial protective effect on oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cells injury through increasing ATP production and maintaining mitochondrial DNA (mtDNA) content. The mechanism study revealed that PTA selectively induced pro-apoptotic protein Bax degradation, without affecting other Bcl-2 family members such as Bcl-2, Bcl-xl, Bad, Puma, Bid, Bim, and Bik. In addition, we found that PTA promoted the association of autophagosomal marker LC3B to Bax for its degradation via an autophagy-dependent manner but not the ubiquitin-proteasome pathway. Collectively, our findings offered a new pharmacological strategy for maintaining mitochondrial function by inducing autophagic degradation of Bax and also provided a novel drug candidate against ischemic neuronal injury.
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PMID:Protosappanin A Maintains Neuronal Mitochondrial Homeostasis through Promoting Autophagic Degradation of Bax. 3322 85


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