Deferasirox protects against hydrogen peroxide-induced cell apoptosis by inhibiting ubiquitination and degradation of p21WAF1/CIP1.

Abstract

Deferasirox (DFX) is an iron chelator approved for the treatment of iron overload diseases. However, the role of DFX in oxidative stress-induced cell apoptosis and the exact molecular mechanisms underlying these processes remain poorly understood and require further investigation. In this study, we found that DFX rendered resistant to H2O2-induced apoptosis in HEK293T cells, reduced the intracellular levels of the labile iron pool (LIP) and oxidative stress induced by H2O2. Furthermore, DFX inhibited the ubiquitination and degradation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) via modulation of the interaction of p21 with SCF-Skp2. DFX also showed the inhibition effect on the activation of c-Jun N-terminal kinase (JNK), pro-caspase-3 and related mitochondrial apoptosis pathway induced by H2O2. These results provide novel insights into the molecular mechanism underpinning iron-mediated oxidative stress and apoptosis, and they may represent a promising target for therapeutic interventions in related pathological conditions.

• Authors: Junhua Miao, Mutao Xu, Yuhuan Kuang, Shuhong Pan, Jianyuan Hou, Pengxiu Cao, Xianglin Duan, Yanzhong Chang, Habelhah Hasem, Nan Zhou, Ke Tan, Yumei Fan
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 524 Issue 3 Pg. 736-743 (04 09 2020) ISSN: 1090-2104 [Electronic] United States
• PMID: 32035614 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Cyclin-Dependent Kinase Inhibitor p21
• Ubiquitin
• Hydrogen Peroxide
• Iron
• JNK Mitogen-Activated Protein Kinases
• Caspase 3
• Deferasirox

Topics

• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Cytoprotection (drug effects)
• Deferasirox (pharmacology)
• HEK293 Cells
• Humans
• Hydrogen Peroxide
• Iron (metabolism)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Mitochondria (drug effects, metabolism)
• Oxidative Stress (drug effects)
• Proteolysis (drug effects)
• Signal Transduction (drug effects)
• Ubiquitin (metabolism)
• Ubiquitination (drug effects)
• Up-Regulation (drug effects)