scholarly journals Targeting Glutathione Metabolism: Partner in Crime in Anticancer Therapy

Nutrients ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1926 ◽  
Author(s):  
Enrico Desideri ◽  
Fabio Ciccarone ◽  
Maria Rosa Ciriolo
Keyword(s):  
Therapeutic Strategy ◽  
State Level ◽  
Anticancer Therapy ◽  
Chemotherapeutic Agents ◽  
Glutathione Metabolism ◽  
Low Molecular Weight ◽  
Steady State Level ◽  
Synthetic Lethal ◽  
Synthetic Lethal Interactions

Glutathione (GSH) is the predominant low-molecular-weight antioxidant with a ubiquitous distribution inside the cell. The steady-state level of cellular GSH is dependent on the balance between synthesis, hydrolysis, recycling of glutathione disulphide (GSSG) as well as cellular extrusion of reduced, oxidized, or conjugated-forms. The augmented oxidative stress typical of cancer cells is accompanied by an increase of glutathione levels that confers them growth advantage and resistance to a number of chemotherapeutic agents. Targeting glutathione metabolism has been widely investigated for cancer treatment although GSH depletion as single therapeutic strategy has resulted largely ineffective if compared with combinatorial approaches. In this review, we circumstantiate the role of glutathione in tumour development and progression focusing on how interfering with different steps of glutathione metabolism can be exploited for therapeutic purposes. A dedicated section on synthetic lethal interactions with GSH modulators will highlight the promising option of harnessing glutathione metabolism for patient-directed therapy in cancer.

scholarly journals Nckβ Adapter Controls Neuritogenesis by Maintaining the Cellular Paxillin Level

2007 ◽  
Vol 27 (17) ◽  
pp. 6001-6011 ◽  
Author(s):  
Shengxi Guan ◽  
Mei Chen ◽  
David Woodley ◽  
Wei Li
Keyword(s):  
Pc12 Cells ◽  
Cortical Neurons ◽  
State Level ◽  
Cell Types ◽  
Steady State Level ◽  
Down Regulation ◽  
Evolutionarily Conserved ◽  
Rat Cortical Neurons ◽  
Interfering Rna

ABSTRACT The SH2/SH3 adapter Nck has an evolutionarily conserved role in neurons, linking the cell surface signals to actin cytoskeleton-mediated responses. The mechanism, however, remains poorly understood. We have investigated the role of Nck/Nckα/Nck1 versus Grb4/Nckβ/Nck2 side-by-side in the process of mammalian neuritogenesis. Here we show that permanent genetic silencing of Nckβ, but not Nckα, completely blocked nerve growth factor-induced neurite outgrowth in PC12 cells and dramatically disrupted the axon and dendrite tree in primary rat cortical neurons. By screening for changes among the components reportedly present in complex with Nck, we found that the steady-state level of paxillin was significantly reduced in Nckβ knockdown, but not Nckα knockdown, neurons. Interestingly, Nckβ knockdown did not affect the paxillin level in glial cells and several other cell types of various tissue origins. Genetic silencing of paxillin blocked neuritogenesis, just like Nckβ knockdown. Reintroducing a nondegradable Nckβ into Nckβ short interfering RNA-expressing PC12 cells rescued paxillin from down-regulation and allowed the resumption of neuritogenesis. Forced expression of paxillin in Nckβ knockdown PC12 also rescued its capacity for neuritogenesis. Finally, Nckβ, but not Nckα, binds strongly to paxillin and treatment of the neurons with proteosome inhibitors prevented paxillin down-regulation in Nckβ knockdown neurons. Thus, Nckβ maintains paxillin stability during neuritogenesis.

scholarly journals The Schizosaccharomyces pombe dim1+ Gene Interacts with the Anaphase-Promoting Complex or Cyclosome (APC/C) Component lid1+ and Is Required for APC/C Function

1999 ◽  
Vol 19 (4) ◽  
pp. 2535-2546 ◽  
Author(s):  
Lynne D. Berry ◽  
Anna Feoktistova ◽  
Melanie D. Wright ◽  
Kathleen L. Gould
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Chromosome Segregation ◽  
State Level ◽  
Temperature Sensitive ◽  
Restrictive Temperature ◽  
Anaphase Promoting Complex ◽  
Synthetic Lethal ◽  
C Complex ◽  
Mutant Cells

ABSTRACT The Schizosaccharomyces pombe dim1 + gene is required for entry into mitosis and for chromosome segregation during mitosis. To further understand dim1p function, we undertook a synthetic lethal screen with the temperature-sensitive dim1-35 mutant and isolated lid (for lethal in dim1-35) mutants. Here, we describe the temperature-sensitive lid1-6mutant. At the restrictive temperature of 36°C, lid1-6mutant cells arrest with a “cut” phenotype similar to that ofcut4 and cut9 mutants. An epitope-tagged version of lid1p is a component of a multiprotein ∼20S complex; the presence of lid1p in this complex depends upon functionalcut9 +. lid1p-myc coimmunoprecipitates with several other proteins, including cut9p and nuc2p, and the presence of cut9p in a 20S complex depends upon the activity oflid1 +. Further, lid1 +function is required for the multiubiquitination of cut2p, an anaphase-promoting complex or cyclosome (APC/C) target. Thus, lid1p is a component of the S. pombe APC/C. In dim1mutants, the abundances of lid1p and the APC/C complex decline significantly, and the ubiquitination of an APC/C target is abolished. These data suggest that at least one role of dim1p is to maintain or establish the steady-state level of the APC/C.

Steady-state level of kit ligand mRNA in goat ovaries and the role of kit ligand in preantral follicle survival and growth in vitro

2009 ◽  
Vol 77 (3) ◽  
pp. 231-240 ◽  
Author(s):  
Juliana J.H. Celestino ◽  
Jamily B. Bruno ◽  
Isabel B. Lima-Verde ◽  
Maria Helena T. Matos ◽  
Mércia Viviane A. Saraiva ◽  
...  
Keyword(s):  
Steady State ◽  
State Level ◽  
Steady State Level ◽  
Preantral Follicle ◽  
Kit Ligand ◽  
Survival And Growth

scholarly journals MYC Oncogene Contributions to Release of Cell Cycle Brakes

Genes ◽  
2019 ◽  
Vol 10 (3) ◽  
pp. 244 ◽  
Author(s):  
Lucía García-Gutiérrez ◽  
María Dolores Delgado ◽  
Javier León
Keyword(s):  
Cell Cycle ◽  
Transcriptional Level ◽  
Synthetic Lethal ◽  
Myc Oncogene ◽  
Synthetic Lethal Interactions ◽  
A Cell ◽  
Functional Inactivation ◽  
P27 Gene ◽  
Cell Cycle Inhibitors

Promotion of the cell cycle is a major oncogenic mechanism of the oncogene c-MYC (MYC). MYC promotes the cell cycle by not only activating or inducing cyclins and CDKs but also through the downregulation or the impairment of the activity of a set of proteins that act as cell-cycle brakes. This review is focused on the role of MYC as a cell-cycle brake releaser i.e., how MYC stimulates the cell cycle mainly through the functional inactivation of cell cycle inhibitors. MYC antagonizes the activities and/or the expression levels of p15, ARF, p21, and p27. The mechanism involved differs for each protein. p15 (encoded by CDKN2B) and p21 (CDKN1A) are repressed by MYC at the transcriptional level. In contrast, MYC activates ARF, which contributes to the apoptosis induced by high MYC levels. At least in some cells types, MYC inhibits the transcription of the p27 gene (CDKN1B) but also enhances p27’s degradation through the upregulation of components of ubiquitin ligases complexes. The effect of MYC on cell-cycle brakes also opens the possibility of antitumoral therapies based on synthetic lethal interactions involving MYC and CDKs, for which a series of inhibitors are being developed and tested in clinical trials

scholarly journals Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy

Oncogene ◽  
2021 ◽  
Author(s):  
Marek Wanior ◽  
Andreas Krämer ◽  
Stefan Knapp ◽  
Andreas C. Joerger
Keyword(s):  
Therapeutic Strategy ◽  
Synthetic Lethality ◽  
Chromatin Remodelling ◽  
Regulatory Proteins ◽  
Chemical Probes ◽  
Synthetic Lethal ◽  
Anticancer Effects ◽  
Synthetic Lethal Interactions ◽  
Genomic Studies ◽  
Encoding Genes

AbstractMulti-subunit ATPase-dependent chromatin remodelling complexes SWI/SNF (switch/sucrose non-fermentable) are fundamental epigenetic regulators of gene transcription. Functional genomic studies revealed a remarkable mutation prevalence of SWI/SNF-encoding genes in 20–25% of all human cancers, frequently driving oncogenic programmes. Some SWI/SNF-mutant cancers are hypersensitive to perturbations in other SWI/SNF subunits, regulatory proteins and distinct biological pathways, often resulting in sustained anticancer effects and synthetic lethal interactions. Exploiting these vulnerabilities is a promising therapeutic strategy. Here, we review the importance of SWI/SNF chromatin remodellers in gene regulation as well as mechanisms leading to assembly defects and their role in cancer development. We will focus in particular on emerging strategies for the targeted therapy of SWI/SNF-deficient cancers using chemical probes, including proteolysis targeting chimeras, to induce synthetic lethality.

scholarly journals A synthetic lethal screen identifies HDAC4 as a potential target in MELK overexpressing cancers

2021 ◽  
Author(s):  
Lin Zhou ◽  
Siqi Zheng ◽  
Fernando R Rosas Bringas ◽  
Bjorn Bakker ◽  
Judith E Simon ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Mammalian Cells ◽  
Leucine Zipper ◽  
Chemotherapy Resistance ◽  
Synthetic Lethal ◽  
Ubiquitin Ligase Complex ◽  
Synthetic Lethal Interactions ◽  
Histone Deacetylase 4 ◽  
A Subunit

Abstract Maternal embryonic leucine zipper kinase (MELK) is frequently overexpressed in cancer, but the role of MELK in cancer is still poorly understood. MELK was shown to have roles in many cancer-associated processes including tumor growth, chemotherapy resistance, and tumor recurrence. To determine whether the frequent overexpression of MELK can be exploited in therapy, we performed a high-throughput screen using a library of Saccharomyces cerevisiae mutants to identify genes whose functions become essential when MELK is overexpressed. We identified two such genes: LAG2 and HDA3. LAG2 encodes an inhibitor of the Skp, Cullin, F-box containing (SCF) ubiquitin-ligase complex, while HDA3 encodes a subunit of the HDA1 histone deacetylase complex. We find that one of these synthetic lethal interactions is conserved in mammalian cells, as inhibition of a human homolog of HDA3 (Histone Deacetylase 4, HDAC4) is synthetically toxic in MELK overexpression cells. Altogether, our work identified a novel potential drug target for tumors that overexpress MELK.

scholarly journals A Pathogenic CytochromebMutation Reveals New Interactions between Subunits of the Mitochondrialbc1Complex

2002 ◽  
Vol 277 (51) ◽  
pp. 49397-49402 ◽  
Author(s):  
Yann Saint-Georges ◽  
Nathalie Bonnefoy ◽  
Jean Paul di Rago ◽  
Stephane Chiron ◽  
Geneviève Dujardin
Keyword(s):  
Steady State ◽  
High Temperature ◽  
State Level ◽  
Energy Transduction ◽  
Steady State Level ◽  
Catalytic Subunits ◽  
Suppressor Mutations ◽  
Human Cytochrome ◽  
New Interactions

Energy transduction in mitochondria involves five oligomeric complexes embedded within the inner membrane. They are composed of catalytic and noncatalytic subunits, the role of these latter proteins often being difficult to assign. One of these complexes, thebc1complex, is composed of three catalytic subunits including cytochromeband seven or eight noncatalytic subunits. Recently, several mutations in the human cytochromebgene have been linked to various diseases. We have studied in detail the effects of a cardiomyopathy generating mutationG252Din yeast. This mutation disturbs the biogenesis of thebc1complex at 36 °C and decreases the steady-state level of the noncatalytic subunit Qcr9p. In addition, theG252Dmutation and the deletion ofQCR9show synergetic defects that can be partially bypassed by suppressor mutations at position 252 and by a new cytochromebmutation,P174T. Altogether, our results suggest that the supernumerary subunit Qcr9p enhances or stabilizes the interactions between the catalytic subunits, this role being essential at high temperature.

scholarly journals Improper Coordination of BamA and BamD Results in Bam Complex Jamming by a Lipoprotein Substrate

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Muralidhar Tata ◽  
Anna Konovalova
Keyword(s):  
Genetic Analysis ◽  
Outer Membrane ◽  
Outer Membrane Proteins ◽  
Synthetic Lethal ◽  
Bam Complex ◽  
Synthetic Lethal Interactions ◽  
Bona Fide ◽  
Redundant Functions ◽  
Kinetics Of

ABSTRACT The β-barrel assembly machinery, the Bam complex, is central to the biogenesis of integral outer membrane proteins (OMPs) as well as OMP-dependent surface-exposed lipoproteins, such as regulator of capsule synthesis protein F (RcsF). Previous genetic analysis established the model that nonessential components BamE and BamB have overlapping, redundant functions to enhance the kinetics of the highly conserved BamA/BamD core. Here we report that BamE plays a specialized nonredundant role in the Bam complex required for surface exposure of RcsF. We show that the lack of bamE, but not bamB, completely abolishes assembly of RcsF/OMP complexes and establish that the inability to assemble RcsF/OMP complexes is a molecular reason underlying all synthetic lethal interactions of ΔbamE. Our genetic analysis and biochemical cross-linking suggest that RcsF accumulates on BamA when BamA cannot engage with BamD because of its limited availability or the incompatible conformation. The role of BamE is to promote proper coordination of RcsF-bound BamA with BamD to complete OMP assembly around RcsF. We show that in the absence of BamE, RcsF is stalled on BamA, thus blocking its function, and we identify the lipoprotein RcsF as a bona fide jamming substrate of the Bam complex. IMPORTANCE The β-barrel assembly machinery, the Bam complex, consists of five components, BamA to -E, among which BamA and BamD are highly conserved and essential. The nonessential components are believed to play redundant roles simply by improving the rate of β-barrel folding. Here we show that BamE contributes a specific and nonoverlapping function to the Bam complex. BamE coordinates BamA and BamD to form a complex between the lipoprotein RcsF and its partner outer membrane β-barrel protein, allowing RcsF to reach the cell surface. In the absence of BamE, RcsF accumulates on BamA, thus blocking the activity of the Bam complex. As the Bam complex is a major antibiotic target in Gram-negative bacteria, the discovery that a lipoprotein can act as a jamming substrate may open the door for development of novel Bam complex inhibitors.

scholarly journals Mapping the human kinome in response to DNA damage

2018 ◽  
Author(s):  
Michel Owusu ◽  
Peter Bannauer ◽  
Athanasios Mourikis ◽  
Alistair Jones ◽  
Joana Ferreira da Silva ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Lines ◽  
Cellular Response ◽  
Chemotherapeutic Agents ◽  
Synthetic Lethal ◽  
Dna Damaging Agents ◽  
Cellular Sensitivity ◽  
Synthetic Lethal Interactions ◽  
Human Kinome ◽  
Repair Pathways

SummaryWe provide a catalog for the effects of the human kinome on cell survival in response to DNA damaging agents, selected to cover all major DNA repair pathways. By treating 313 kinase-deficient cell lines with ten diverse DNA damaging agents, including seven commonly used chemotherapeutics, we were able to identify kinase specific vulnerabilities and resistances. In order to identify novel synthetic lethal interactions, we investigate the cellular response to carmustine for 25 cell lines, by establishing a phenotypic FACS assay designed to mechanistically investigate and validate gene-drug interactions. We show apoptosis, cell cycle, DNA damage and proliferation after alkylation or crosslink-induced damage for selected cell lines and rescue the cellular sensitivity of DYRK4, EPHB6, MARK3, PNCK as a proof of principle for our study. Our data suggest that some cancers with inactivated DYRK4, EPHB6, MARK3 or PNCK gene could be particularly vulnerable to treatment by alkylating chemotherapeutic agents carmustine or temozolomide.

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