Deferasirox induces cyclin D1 degradation and apoptosis in mantle cell lymphoma in a reactive oxygen species- and GSK3β-dependent mechanism.
Apoptosis
/ drug effects
Cell Line, Tumor
Cyclin D1
/ metabolism
Deferasirox
/ pharmacology
Glycogen Synthase Kinase 3 beta
/ metabolism
Humans
Iron Chelating Agents
/ pharmacology
Lymphoma, Mantle-Cell
/ drug therapy
Proteolysis
/ drug effects
Reactive Oxygen Species
/ metabolism
Tumor Cells, Cultured
GSK3β
ROS
cyclin D1
deferasirox
mantle cell lymphoma
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
15
07
2020
revised:
12
11
2020
accepted:
24
11
2020
pubmed:
2
2
2021
medline:
16
6
2021
entrez:
1
2
2021
Statut:
ppublish
Résumé
Mantle cell lymphoma (MCL) is a difficult-to-treat B-cell malignancy characterized by cyclin D1 (CD1) overexpression. Targeting CD1 in MCL has been shown to be of therapeutic significance. However, treatment of MCL remains challenging since patients are still subject to early and frequent relapse of the disease. To ensure their high proliferation rate, tumour cells have increased iron needs, making them more susceptible to iron deprivation. Indeed, several iron chelators proved to be effective anti-cancer agents. In this study, we demonstrate that the clinically approved iron chelator deferasirox (DFX) exerts an anti-tumoural effect in MCL cell lines and patient cells. The exposure of MCL cells to clinically feasible concentrations of DFX resulted in growth inhibition, cell cycle arrest and induction of apoptosis. We show that DFX unfolds its cytotoxic effect by a rapid induction of reactive oxygen species (ROS) that leads to oxidative stress and severe DNA damage and by triggering CD1 proteolysis in a mechanism that requires its phosphorylation on T286 by glycogen synthase kinase-3β (GSK3β). Moreover, we demonstrate that DFX mediates CD1 proteolysis by repressing the phosphatidylinositol 3-kinase (PI3K)/AKT/GSK3β pathway via ROS generation. Our data suggest DFX as a potential therapeutic option for MCL and paves the way for more treatment options for these patients.
Substances chimiques
CCND1 protein, human
0
Iron Chelating Agents
0
Reactive Oxygen Species
0
Cyclin D1
136601-57-5
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Deferasirox
V8G4MOF2V9
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
747-760Informations de copyright
© 2020 British Society for Haematology and John Wiley & Sons Ltd.
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