PUBLICATION
Cytotoxic unsaturated electrophilic compounds commonly target the ubiquitin proteasome system
- Authors
- Selvaraju, K., Mofers, A., Pellegrini, P., Salomonsson, J., Ahlner, A., Morad, V., Hillert, E.K., Espinosa, B., Arnér, E.S.J., Jensen, L., Malmström, J., Turkina, M.V., D'Arcy, P., Walters, M.A., Sunnerhagen, M., Linder, S.
- ID
- ZDB-PUB-190711-5
- Date
- 2019
- Source
- Scientific Reports 9: 9841 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Antineoplastic Agents/administration & dosage*
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology
- Catalytic Domain
- Cell Line, Tumor
- Cell Survival/drug effects
- Drug Screening Assays, Antitumor
- HCT116 Cells
- HeLa Cells
- Humans
- MCF-7 Cells
- Proteasome Endopeptidase Complex/chemistry
- Proteasome Endopeptidase Complex/metabolism
- Proteasome Inhibitors/administration & dosage*
- Proteasome Inhibitors/chemistry
- Proteasome Inhibitors/pharmacology
- Protein Binding
- Small Molecule Libraries/administration & dosage*
- Small Molecule Libraries/chemistry
- Small Molecule Libraries/pharmacology
- Ubiquitin Thiolesterase/chemistry
- Ubiquitin Thiolesterase/metabolism*
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 31285509 Full text @ Sci. Rep.
Citation
Selvaraju, K., Mofers, A., Pellegrini, P., Salomonsson, J., Ahlner, A., Morad, V., Hillert, E.K., Espinosa, B., Arnér, E.S.J., Jensen, L., Malmström, J., Turkina, M.V., D'Arcy, P., Walters, M.A., Sunnerhagen, M., Linder, S. (2019) Cytotoxic unsaturated electrophilic compounds commonly target the ubiquitin proteasome system. Scientific Reports. 9:9841.
Abstract
A large number of natural products have been advocated as anticancer agents. Many of these compounds contain functional groups characterized by chemical reactivity. It is not clear whether distinct mechanisms of action can be attributed to such compounds. We used a chemical library screening approach to demonstrate that a substantial fraction (~20%) of cytotoxic synthetic compounds containing Michael acceptor groups inhibit proteasome substrate processing and induce a cellular response characteristic of proteasome inhibition. Biochemical and structural analyses showed binding to and inhibition of proteasome-associated cysteine deubiquitinases, in particular ubiquitin specific peptidase 14 (USP14). The results suggested that compounds bind to a crevice close to the USP14 active site with modest affinity, followed by covalent binding. A subset of compounds was identified where cell death induction was closely associated with proteasome inhibition and that showed significant antineoplastic activity in a zebrafish embryo model. These findings suggest that proteasome inhibition is a relatively common mode of action by cytotoxic compounds containing Michael acceptor groups and help to explain previous reports on the antineoplastic effects of natural products containing such functional groups.
Errata / Notes
This article is corrected by ZDB-PUB-220906-181.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping