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The NEDD8-activating enzyme inhibitor pevonedistat activates the eIF2α and mTOR pathways inducing UPR-mediated cell death in acute lymphoblastic leukemia.
- Source :
-
Leukemia research [Leuk Res] 2016 Nov; Vol. 50, pp. 1-10. Date of Electronic Publication: 2016 Sep 05. - Publication Year :
- 2016
-
Abstract
- Acute lymphoblastic leukemia (ALL) is the leading cause of cancer-related death in children, and cure rates for adults remain dismal. Further, effective treatment strategies for relapsed/refractory ALL remain elusive. We previously uncovered that ALL cells are prone to apoptosis via endoplasmic reticulum (ER) stress/unfolded protein response (UPR)-mediated mechanisms. We investigated the antineoplastic activity of pevonedistat <superscript>®</superscript> , a novel NEDD8-activating enzyme inhibitor that targets E3 cullin-RING ligases (CRLs) dependent proteasomal protein degradation, in ALL. Herein, we report that pevonedistat induces apoptosis in ALL cells by dysregulating the translational machinery leading to induction of proteotoxic/ER stress and UPR-mediated cell death. Mechanistically, pevonedistat led to P-eIF2a dephosphorylation causing atypical proteotoxic/ER stress from failure to halt protein translation via the UPR and upregulation of mTOR/p70S6K. Additional studies revealed that pevonedistat re-balanced the homeostasis of pro- and anti-apoptotic proteins to favor cell death through altered expression and/or activity of Mcl-1, NOXA, and BIM, suggesting that pevonedistat has a "priming" effect on ALL by altering the apoptotic threshold through modulation of Mcl-1 activity. Further, we demonstrated that pevonedistat synergizes with selected anti-leukemic agents in vitro, and prolongs survival of NSG mice engrafted with ALL cells, lending support for the use of pevonedistat as part of a multi-agent approach.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents
Cell Death drug effects
Cell Line, Tumor
Cyclopentanes therapeutic use
Endoplasmic Reticulum Stress
Enzyme Inhibitors
Heterografts
Humans
Mice
NEDD8 Protein
Pyrimidines therapeutic use
Cyclopentanes pharmacology
Eukaryotic Initiation Factor-2 metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Pyrimidines pharmacology
TOR Serine-Threonine Kinases metabolism
Ubiquitins antagonists & inhibitors
Unfolded Protein Response drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1873-5835
- Volume :
- 50
- Database :
- MEDLINE
- Journal :
- Leukemia research
- Publication Type :
- Academic Journal
- Accession number :
- 27626202
- Full Text :
- https://doi.org/10.1016/j.leukres.2016.09.007