Deferasirox-Dependent Iron Chelation Enhances Mitochondrial Dysfunction and Restores p53 Signaling by Stabilization of p53 Family Members in Leukemic Cells.

Chiara Calabrese,Silvia Ravera,Muhammad Shahzad Ali,Francesca Napoli,Serena Stanga,Enrico Bracco,Cristina Panuzzo,Alessandro Maglione,Giacomo Andreani,Francesco Frassoni,Jessica Petiti,Giuseppe Saglio,Carmen Fava,Barbara Pergolizzi,Lucrezia Pironi,Patrizia Scaravaglio,Marco De Gobbi,Daniela Cilloni

doi:10.3390/ijms21207674

Abstract

Iron is crucial to satisfy several mitochondrial functions including energy metabolism and oxidative phosphorylation. Patients affected by Myelodysplastic Syndromes (MDS) and acute myeloid leukemia (AML) are frequently characterized by iron overload (IOL), due to continuous red blood cell (RBC) transfusions. This event impacts the overall survival (OS) and it is associated with increased mortality in lower-risk MDS patients. Accordingly, the oral iron chelator Deferasirox (DFX) has been reported to improve the OS and delay leukemic transformation. However, the molecular players and the biological mechanisms laying behind remain currently mostly undefined. The aim of this study has been to investigate the potential anti-leukemic effect of DFX, by functionally and molecularly analyzing its effects in three different leukemia cell lines, harboring or not p53 mutations, and in human primary cells derived from 15 MDS/AML patients. Our findings indicated that DFX can lead to apoptosis, impairment of cell growth only in a context of IOL, and can induce a significant alteration of mitochondria network, with a sharp reduction in mitochondrial activity. Moreover, through a remarkable reduction of Murine Double Minute 2 (MDM2), known to regulate the stability of p53 and p73 proteins, we observed an enhancement of p53 transcriptional activity after DFX. Interestingly, this iron depletion-triggered signaling is enabled by p73, in the absence of p53, or in the presence of a p53 mutant form. In conclusion, we propose a mechanism by which the increased p53 family transcriptional activity and protein stability could explain the potential benefits of iron chelation therapy in terms of improving OS and delaying leukemic transformation.

Highlights

Iron is a cofactor for many biochemical processes including oxidative phosphorylation, oxygen storage, and enzymatic reactions, it is essential for the survival of most types of cells
The analysis of the mitochondria shapes was performed by using the MiNA toolset [54], which allows to obtain parameters to quantitatively capture the morphology of the mitochondrial network
In line with these reports, recent studies described the improved leukemia-free survival in patients affected by acute myeloid leukemia (AML) and Myelodysplastic Syndromes (MDS) treated with iron chelation [9,10,11,12,13]

Summary

Introduction

Iron is a cofactor for many biochemical processes including oxidative phosphorylation, oxygen storage, and enzymatic reactions, it is essential for the survival of most types of cells. Through the generation of intracellular Reactive Oxygen Species (ROS), increases the level of genomic instability and lipid peroxidation and is implicated in several types of cancer [2,3], accelerating disease progression [4] In this scenario, iron deprivation showed beneficial effects on tumors cells in terms of apoptosis and cell cycle arrest [5,6]. Shen and colleagues demonstrated that intracellular iron overload shortens p53 half-life by promoting p53 nuclear export and cytosolic degradation [27,28,29] These data provide insights into tumorigenesis associated to iron excess, suggesting that the p53 family might represent an interesting target to be investigated during iron chelation therapy. They share overlapping functions due to their ability to trans-activate the same genes like cyclin-dependent kinase (CDK) inhibitor (CDKN1A (p21)), Bcl Binding Component 3 (PUMA), and Murine Double Minute 2 (MDM2) [36,37,38]

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Results

Discussion

Conclusion