The histone deacetylase inhibitor cambinol prevents acidic pHe-induced anterograde lysosome trafficking independently of sirtuin activity
| Autor: | Samantha S. Dykes, James A. Cardelli, Ellen Friday, Kevin Pruitt |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
MAPK/ERK pathway
medicine.drug_class Biophysics HDAC histone deacetylase Biochemistry Cathepsin B Troglitazone LAMP-1 lysosome associated membrane protein 1 Lysosome pHe extracellular pH Rab7 medicine Extracellular EIPA ethyl-isopropyl amiloride MTOC microtubule organizing center Lysosome trafficking Tro troglitazone biology Sirtuin 1 Histone deacetylase inhibitor Autophagy Cambinol Cell biology JLA juxtanuclear lysosome aggregation ERK medicine.anatomical_structure Sirtuin SIRT sirtuin biology.protein NHE sodium proton exchanger Research Article Acidic pHe |
| Zdroj: | Biochemistry and Biophysics Reports |
| ISSN: | 2405-5808 |
| Popis: | Common features of the solid tumor microenvironment, such as acidic extracellular pH and growth factors, are known to induce the redistribution of lysosomes from a perinuclear region to a position near the plasma membrane. Lysosome/plasma membrane juxtaposition facilitates invasion by allowing for the release of lysosomal proteases, including cathepsin B, which contribute to matrix degradation. In this study we identified the sirtuin 1/sirtuin 2 (SIRT1/2) inhibitor cambinol acts as a drug that inhibits lysosome redistribution and tumor invasion. Treatment of cells with cambinol resulted in a juxtanuclear lysosome aggregation (JLA) similar to that seen upon treatment with the PPARγ agonist, troglitazone (Tro). Like Tro, cambinol required the activity of ERK1/2 in order to induce this lysosome clustering phenotype. However, cambinol did not require the activity of Rab7, suggesting that this drug causes JLA by a mechanism different from what is known for Tro. Additionally, cambinol-induced JLA was not a result of autophagy induction. Further investigation revealed that cambinol triggered JLA independently of its activity as a SIRT1/2 inhibitor, suggesting that this drug could have effects in addition to SIRT1/2 inhibition that could be developed into a novel anti-cancer therapy. Highlights • Cambinol prevents acidic pHe-induced anterograde lysosome trafficking. • Cambinol-mediated lysosome aggregation is not dependent on sirtuin activity. • ERK1/2 activity is necessary for cambinol-driven juxtanuclear lysosome aggregation. |
| Databáze: | OpenAIRE |
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