Oxidative Stress-Mediated Regulation of Proteasome Complexes

Aiken, Charity T.; Kaake, Robyn M.; Wang, Xiaorong; Huang, Lan

doi:10.1074/mcp.m110.006924

Cited by 276 publications

(190 citation statements)

References 176 publications

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“…4D, left panel, supplemental Table 5). Because an increase of proteasome activity usually is a cytoprotective response of cells to degrade misfolded proteins (41), these data suggest that the PDT treatment induces protein misfolding stress in primary AML cells. Consistent with this observation, in an independent GSEA analysis using a collection of REACTOME gene sets, we also found that the "Unfolded protein response" pathway is significantly up-regulated upon PDT treatment (Fig.…”

Section: Pdt Regimen Does Not Affect Nf-b Signaling But Induces Stronmentioning

confidence: 78%

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Pei¹,

Minhajuddin²,

D’Alessandro

et al. 2016

Journal of Biological Chemistry

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Although multidrug approaches to cancer therapy are common, few strategies are based on rigorous scientific principles. Rather, drug combinations are largely dictated by empirical or clinical parameters. In the present study we developed a strategy for rational design of a regimen that selectively targets human acute myelogenous leukemia (AML) stem cells. As a starting point, we used parthenolide, an agent shown to target critical mechanisms of redox balance in primary AML cells. Next, using proteomic, genomic, and metabolomic methods, we determined that treatment with parthenolide leads to induction of compensatory mechanisms that include up-regulated NADPH production via the pentose phosphate pathway as well as activation of the Nrf2-mediated oxidative stress response pathway. Using this knowledge we identified 2-deoxyglucose and temsirolimus as agents that can be added to a parthenolide regimen as a means to inhibit such compensatory events and thereby further enhance eradication of AML cells. We demonstrate that the parthenolide, 2-deoxyglucose, temsirolimus (termed PDT) regimen is a potent means of targeting AML stem cells but has little to no effect on normal stem cells. Taken together our findings illustrate a comprehensive approach to designing combination anticancer drug regimens.Numerous studies have documented the biological complexity of human tumor cell populations in which genetic, epigenetic, biochemical, and metabolic properties can often be quite heterogeneous (1, 2). As a result, complicated multidrug regimens are often employed to target various components of tumor biology and/or acquired drug resistance (3, 4). However, the rationale behind the design of multidrug regimens is usually inconsistent and often driven by pragmatism more than scientific rigor. Thus, establishing more effective means by which to identify optimal drug regimens is an important priority, particularly with the recent emergence of a broad range of targeted agents.

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Section: Pdt Regimen Does Not Affect Nf-b Signaling But Induces Stronmentioning

confidence: 78%

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Pei¹,

Minhajuddin²,

D’Alessandro

et al. 2016

Journal of Biological Chemistry

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“…These proteomic biomarkers implied the differential effects of V. anguillarum to M. galloprovincialis compared with those proteomic biomarkers induced by M. luteus. The proteasomes are involved in the proteasomal degradation pathway and can respond to environmental stresses [53]. The significant up-regulation of proteasome subunit beta type-1 indicated the defensive response of M. galloprovincialis to V. anguillarum challenge, which was similarly indicated by the up-regulated proteasome beta 7 subunit-like in M. luteuschallenged mussel samples, resulting in elevated amino acids such as lysine, leucine and valine (Fig.…”

Section: Effects Of M Luteus and V Anguillarum On The Proteome Of Hmentioning

confidence: 91%

Proteomic and metabolomic responses in hepatopancreas of Mytilus galloprovincialis challenged by Micrococcus luteus and Vibrio anguillarum

Wei

et al. 2013

Journal of Proteomics

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The outbreak of pathogens can induce diseases and lead to massive mortalities of aquaculture animals including fish, mollusk and shrimp. In this work, the responses induced by Micrococcus luteus and Vibrio anguillarum were investigated in hepatopancreas of mussel Mytilus galloprovincialis using proteomics and metabolomics. Metabolic biomarkers demonstrated that M. luteus and V. anguillarum injections could induce osmotic stress and disturbance in energy metabolism. And the uniquely and more markedly altered metabolic biomarkers (glutamine, succinate, aspartate, glucose, ATP, homarine and tyrosine) indicated that V. anguillarum could cause more severe disturbances in osmotic regulation and energy metabolism. The differentially altered proteins meant that M. luteus and V. anguillarum induced different effects in mussels. However, the common proteomic biomarkers, arginine kinase and small heat shock protein, demonstrated that these two bacteria induced similar effects including oxidative stress and disturbance in energy metabolism in M. galloprovincialis. In addition, some metabolic biomarkers, ATP and glutamine, were confirmed by related proteins including arginine kinase, ATP synthase, nucleoside diphosphate kinase and glutamine synthetase in bacteria-challenged mussels.This study demonstrated that proteomics and metabolomics could provide an insightful view into the effects of environmental pathogens to the marine mussel M. galloprovincialis. Biological significanceThe outbreak of pathogens can lead to diseases and massive mortalities of aquaculture animals including fish, mollusk and shrimp. The mussel M. galloprovincialis distributes widely along the Bohai coast and is popularly consumed as delicious seafood by local residents. This bivalve has become one of the important species in marine aquaculture industry in China. Therefore a study on pathogen-induced effects is necessary. In the present study, an integrated metabolomic and proteomic approach was used to elucidate the differential effects induced by the representative Gram-positive (M. luteus) and Gram-negative (V. anguillarum) bacteria in M. galloprovincialis.

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“…Proteasome homeostasis is dynamic and delicately regulated upon stress [50,51]. Proteasomal inhibition was found to activate Nrf1- [52] or Nrf2-mediated [53] transcription of some proteasome subunits, which gave rise to the so-called "proteasome bounce-back response".…”

Section: Btz Stabilized Proteasome Subunits Psmc1 and Proteasome Assementioning

confidence: 99%

Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

Tao

Yang

et al. 2014

Cell Res

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Global change in protein turnover (protein degradome) constitutes a central part of cellular responses to intrinsic or extrinsic stimuli. However, profiling protein degradome remains technically challenging. Recently, inhibition of the proteasome, e.g., by using bortezomib (BTZ), has emerged as a major chemotherapeutic strategy for treating multiple myeloma and other human malignancies, but systematic understanding of the mechanisms for BTZ drug action and tumor drug resistance is yet to be achieved. Here we developed and applied a dual-fluorescence-based Protein Turnover Assay (ProTA) to quantitatively profile global changes in human protein degradome upon BTZ-induced proteasomal inhibition. ProTA and subsequent network analyses delineate potential molecular basis for BTZ action and tumor drug resistance in BTZ chemotherapy. Finally, combined use of BTZ with drugs targeting the ProTA-identified key genes or pathways in BTZ action reduced BTZ resistance in multiple myeloma cells. Remarkably, BTZ stabilizes proteasome subunit PSMC1 and proteasome assembly factor PSMD10, suggesting a previously under-appreciated mechanism for regulating proteasome homeostasis. Therefore, ProTA is a novel tool for profiling human protein degradome to elucidate potential mechanisms of drug action and resistance, which might facilitate therapeutic development targeting proteostasis to treat human disorders.

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Oxidative Stress-Mediated Regulation of Proteasome Complexes

Cited by 276 publications

References 176 publications

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Proteomic and metabolomic responses in hepatopancreas of Mytilus galloprovincialis challenged by Micrococcus luteus and Vibrio anguillarum

Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

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