PUBLICATION
Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570
- Authors
- Pellegrini, P., Selvaraju, K., Faustini, E., Mofers, A., Zhang, X., Ternerot, J., Schubert, A., Linder, S., D Arcy, P.
- ID
- ZDB-PUB-210220-51
- Date
- 2020
- Source
- International Journal of Molecular Sciences 21(13): (Journal)
- Registered Authors
- Keywords
- acute lymphocytic leukemia, bortezomib, proteasome, translation
- MeSH Terms
-
- Animals
- Apoptosis/drug effects
- Azepines/pharmacology*
- Benzylidene Compounds/pharmacology*
- Bortezomib/pharmacology
- Cell Line, Tumor
- Deubiquitinating Enzymes/antagonists & inhibitors*
- Deubiquitinating Enzymes/metabolism*
- Endoplasmic Reticulum Stress/drug effects*
- Heat-Shock Proteins/metabolism
- Humans
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism*
- Proteasome Endopeptidase Complex/drug effects
- Proteasome Endopeptidase Complex/metabolism
- Proteasome Inhibitors/pharmacology
- Protein Folding/drug effects
- Transcription Factor CHOP/metabolism
- Unfolded Protein Response/drug effects
- Zebrafish
- PubMed
- 32635430 Full text @ Int. J. Mol. Sci.
Citation
Pellegrini, P., Selvaraju, K., Faustini, E., Mofers, A., Zhang, X., Ternerot, J., Schubert, A., Linder, S., D Arcy, P. (2020) Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570. International Journal of Molecular Sciences. 21(13):.
Abstract
The proteasome is a validated target of cancer therapeutics. Inhibition of proteasome activity results in the activation of the unfolded protein response (UPR) characterized by phosphorylation of eukaryotic initiation factor 2α (eIF2α), global translational arrest, and increased expression of the proapoptotic CHOP (C/EBP homologous protein) protein. Defects in the UPR response has been reported to result in altered sensitivity of tumor cells to proteasome inhibitors. Here, we characterized the effects of the deubiquitinase (DUB) inhibitor VLX1570 on protein homeostasis, both at the level of the UPR and on protein translation, in acute lymphoblastic leukemia (ALL). Similar to the 20S inhibitor bortezomib, VLX1570 induced accumulation of polyubiquitinated proteins and increased expression of the chaperone Grp78/Bip in ALL cells. Both compounds induced cleavage of PARP (Poly (ADP-ribose) polymerase) in ALL cells, consistent with induction of apoptosis. However, and in contrast to bortezomib, VLX1570 treatment resulted in limited induction of the proapoptotic CHOP protein. Translational inhibition was observed by both bortezomib and VLX1570. We report that in distinction to bortezomib, suppression of translation by VXL1570 occurred at the level of elongation. Increased levels of Hsc70/Hsp70 proteins were observed on polysomes following exposure to VLX1570, possibly suggesting defects in nascent protein folding. Our findings demonstrate apoptosis induction in ALL cells that appears to be uncoupled from CHOP induction, and show that VLX1570 suppresses protein translation by a mechanism distinct from that of bortezomib.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping