LC3A Silencing Hinders Aggresome Vimentin Cage Clearance in Primary Choroid Plexus Carcinoma

Nassar, Marwa; Samaha, Heba; Ghabriel, Myret; Yehia, Maha; Taha, Hala; Salem, Sherin; Shaaban, Khaled; Omar, Mariam; Ahmed, Nabil; El‐Naggar, Shahenda

doi:10.1038/s41598-017-07403-5

Cited by 17 publications

(9 citation statements)

References 43 publications

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“…Choroid plexus carcinoma cell line CCHE-45 was then used to test the effect of the test HDAC6 inhibitor 10a on cell proliferation. CCHE-45 cell line is characterised by constitutive formation of aggresomes 41 , which are inclusion bodies for highly misfolded proteins formed by the collapse of the intermediate filament vimentin. Protein aggregates that are unable to be degraded by the proteasome are shuttled along the microtubules to the aggresomes assisted by dynein motor proteins and HDAC6 75 .…”

Section: Resultsmentioning

confidence: 99%

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Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma

Kassab

Mowafy

Alserw

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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Histone deacetylase 6 (HDAC6) is an attractive target for cancer therapeutic intervention. Selective HDAC6 inhibitors is important to minimise the side effects of pan inhibition. Thus, new class of hydroxamic acid-based derivatives were designed on structural basis to perform preferential activity against HDAC6 targeting solid tumours. Interestingly, 1-benzylbenzimidazole-2-thio- N -hydroxybutanamide 10a showed impressive preference with submicromolar potency against HDAC6 (IC 50 = 510 nM). 10a showed cytotoxic activity with interesting profile against CCHE-45 at (IC 50 = 112.76 µM) when compared to standard inhibitor Tubacin (IC 50 = 20 µM). Western blot analysis of acetylated-α-tubulin verified the HDAC6 inhibiting activity of 10a . Moreover, the insignificant difference in acetylated-α-tubulin induced by 10a and Tubacin implied the on-target cytotoxic activity of 10a . Docking of 10a in the binding site of HDAC6 attributed the activity of 10a to π-π stacking with the amino acids of the hydrophobic channel of HDAC6 and capture of zinc metal in bidentate fashion. The therapeutic usefulness besides the on-target activity may define 10a as an interesting safe-lead inhibitor for future development.

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Section: Resultsmentioning

confidence: 99%

“…Established primary Choroid plexus carcinoma (CCHE-45) were cultured as previously described [41], in RPMI-1640 (Lonza, BE-12-702F) supplemented with 10% Fetal Bovine Serum (FBS, Gibco, 12483–020) and 100 U/ml penicillin and 100 µg/ml streptomycin (Lonza, DE17-602F). Cells were maintained at 37 °C in a 5% CO 2 humidified atmosphere.…”

Section: Methodsmentioning

confidence: 99%

Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma

Kassab

Mowafy

Alserw

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…In addition, intermediate filament proteins bearing other modifications related to oxidative stress-induced cell damage, like carbamylation, can show increased immunogenicity and behave as autoantigens in autoimmune disease [38]. On the other hand, vimentin-delimited aggresome structures could help isolating abnormally unfolded or damaged proteins for lysosomal clearance, generally through autophagy [28], [34]. Moreover, intermediate filament proteins could act as decoys or scavengers of oxidants or electrophiles [1], or buffers of phosphate groups [56], serving to limit the effects of stress kinases.…”

Section: Introductionmentioning

confidence: 99%

Vimentin disruption by lipoxidation and electrophiles: Role of the cysteine residue and filament dynamics

2019

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The intermediate filament protein vimentin constitutes a critical sensor for electrophilic and oxidative stress, which induce extensive reorganization of the vimentin cytoskeletal network. Here, we have investigated the mechanisms underlying these effects. In vitro, electrophilic lipids, including 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal (HNE), directly bind to vimentin, whereas the oxidant diamide induces disulfide bond formation. Mutation of the single vimentin cysteine residue (Cys328) blunts disulfide formation and reduces lipoxidation by 15d-PGJ2, but not HNE. Preincubation with these agents differentially hinders NaCl-induced filament formation by wild-type vimentin, with effects ranging from delayed elongation and increased filament diameter to severe impairment of assembly or aggregation. Conversely, the morphology of vimentin Cys328Ser filaments is mildly or not affected. Interestingly, preformed vimentin filaments are more resistant to electrophile-induced disruption, although chemical modification is not diminished, showing that vimentin (lip)oxidation prior to assembly is more deleterious. In cells, electrophiles, particularly diamide, induce a fast and drastic disruption of existing filaments, which requires the presence of Cys328. As the cellular vimentin network is under continuous remodeling, we hypothesized that vimentin exchange on filaments would be necessary for diamide-induced disruption. We confirmed that strategies reducing vimentin dynamics, as monitored by FRAP, including cysteine crosslinking and ATP synthesis inhibition, prevent diamide effect. In turn, phosphorylation may promote vimentin disassembly. Indeed, treatment with the phosphatase inhibitor calyculin A to prevent dephosphorylation intensifies electrophile-induced wild-type vimentin filament disruption. However, whereas a phosphorylation-deficient vimentin mutant is only partially protected from disorganization, Cys328Ser vimentin is virtually resistant, even in the presence of calyculin A. Together, these results indicate that modification of Cys328 and vimentin exchange are critical for electrophile-induced network disruption.

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“…These early aggresomes are cytotoxic and they are surrounded by intermediate cytoskeleton filaments. In the later stage, aggresomes are processed into non-toxic double-membrane autophagosome and degraded in the lysosome [28][29][30][31].…”

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confidence: 99%

Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

Malampati

Song

Tong

et al. 2020

Cells

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Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases in older individuals with specific neuropsychiatric symptoms. It is a proteinopathy, pathologically characterized by the presence of misfolded protein (Aβ and Tau) aggregates in the brain, causing progressive dementia. Increasing studies have provided evidence that the defect in protein-degrading systems, especially the autophagy-lysosome pathway (ALP), plays an important role in the pathogenesis of AD. Recent studies have demonstrated that AD-associated protein aggregates can be selectively recognized by some receptors and then be degraded by ALP, a process termed aggrephagy. In this study, we reviewed the role of aggrephagy in AD development and discussed the strategy of promoting aggrephagy using small molecules for the treatment of AD.

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LC3A Silencing Hinders Aggresome Vimentin Cage Clearance in Primary Choroid Plexus Carcinoma

Cited by 17 publications

References 43 publications

Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma

Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma

Vimentin disruption by lipoxidation and electrophiles: Role of the cysteine residue and filament dynamics

Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

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