Lysosomal accumulation of Masitinib alters autophagy via pH-dependent trapping.
El Sayed, A.; Kluzek, M.; Serwa, R.; Azzi, A.
Show abstract
Masitinib is an oral tyrosine kinase inhibitor developed initially for the treatment of mastocytosis. Preclinical studies suggest that masitinib can modulate mast cell activity and neuroinflammation, making it a potential therapeutic candidate for neurodegenerative diseases. However, clinical outcomes remain inconclusive, which may be linked to a lack of understanding of its molecular mechanism of action and potential off-target effects. Using a panel of cancer cell lines, we found that masitinib suppresses mTORC1 activity while simultaneously inducing AKT phosphorylation. Interestingly, thermal proteome profiling analysis revealed that lysosomal proteins were the most thermally affected by masitinib. Using large unilamellar vesicle systems that mimic the lipid composition and physicochemical environment of lysosomal membranes, we observed that masitinib preferentially accumulates in acidic vesicle membranes, consistent with a pH-dependent trapping mechanism. Furthermore, cellular assays demonstrated that masitinib disrupts autophagy by impairing lysosomal acidification. Together, these findings elucidate the lysosomal accumulation of masitinib, providing a molecular basis for its mechanism of action.
Matching journals
The top 14 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Restricting α-Synuclein Transport into Mitochondria by Inhibition of α-Synuclein-VDAC Complexation as a Potential Therapeutic Target for Parkinson's Disease Treatment 95%
- The Gb3-enriched CD59/flotillin plasma membrane domain regulates host cell invasion by Pseudomonas aeruginosa 94%
- Flotillins affect LPS-induced TLR4 signaling by modulating the trafficking and abundance of CD14 93%
Similar papers in this journal
- Identification of a cardiac glycoside exhibiting favorable brain bioavailability and potency for reducing levels of the cellular prion protein 93%
- A naturally occurring urinary collagen type I alpha 1-derived peptide inhibits collagen type I-induced endothelial cell migration at physiological concentrations 93%
- An optimized workflow for analyzing extracellular vesicles as biomarkers in liver diseases. 93%
Similar papers in this journal
- Transdermal Delivery of Ultradeformable Cationic Liposomes Complexed with miR211-5p (UCL-211) Stabilizes BRAFV600E+ Melanocytic Nevi 94%
- Microvesicles Transfer Mitochondria and Increase Mitochondrial Function in Brain Endothelial Cells 93%
- Increasing phagocytosis of microglia through targeting CD33 with liposomes displaying glycan ligands 93%
Similar papers in this journal
- The SARS-CoV-2 cytopathic effect is blocked with autophagy modulators 92%
- A FRET-based high-throughput screening assay for the discovery of Mycobacterium tuberculosis DNA ADP-ribosylglycohydrolase DarG inhibitors 91%
- Cytoplasmic membrane thinning observed by interfacial dyes is likely a common effect of bactericidal antibiotics 91%
Similar papers in this journal
- Polarized Desmosome and Hemidesmosome Shedding via Exosomes is an Early Indicator of Outer Blood-Retina Barrier Dysfunction 92%
- In vivo-mimicking 3D cultures secrete distinct extracellular vesicles upon cancer cell invasion 92%
- Differentiation of Large Extracellular Vesicles in Oral Fluid: Combined Protocol of Small Force Centrifugation and Pattern Analysis 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.