Perturbation of Iron Metabolism by Cisplatin through Inhibition of Iron Regulatory Protein 2.

Abstract

Cisplatin is classically known to exhibit anticancer activity through DNA damage in the nucleus. Here we found a mechanism by which cisplatin affects iron metabolism, leading to toxicity and cell death. Cisplatin causes intracellular iron deficiency through direct inhibition of the master regulator of iron metabolism, iron regulatory protein 2 (IRP2) with marginal effects on IRP1. Cisplatin, but not carboplatin or transplatin, binds human IRP2 at Cys512 and Cys516 and impairs IRP2 binding to iron-responsive elements of ferritin and transferrin receptor-1 (TfR1) mRNAs. IRP2 inhibition by cisplatin caused ferritin upregulation and TfR1 downregulation leading to sustained intracellular iron deficiency. Cys512/516Ala mutant IRP2 made cells more resistant to cisplatin. Furthermore, combination of cisplatin and the iron chelator desferrioxamine enhanced cytotoxicity through augmented iron depletion in culture and xenograft mouse model. Collectively, cisplatin is an inhibitor of IRP2 that induces intracellular iron deficiency.

• Authors: Masaki Miyazawa, Alexander R Bogdan, Yoshiaki Tsuji
• Journal: Cell chemical biology (Cell Chem Biol) Vol. 26 Issue 1 Pg. 85-97.e4 (01 17 2019) ISSN: 2451-9448 [Electronic] United States
• PMID: 30449675 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Iron
• IREB2 protein, human
• Iron Regulatory Protein 2
• Cisplatin

Topics

• Adolescent
• Adult
• Aged
• Animals
• Antineoplastic Agents (metabolism, pharmacology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Cisplatin (metabolism, pharmacology)
• Drug Screening Assays, Antitumor
• Female
• Fetus
• Humans
• Iron (metabolism)
• Iron Deficiencies
• Iron Regulatory Protein 2 (antagonists & inhibitors, genetics, metabolism)
• Male
• Mice
• Middle Aged
• Molecular Structure
• Neoplasms, Experimental (drug therapy, metabolism, pathology)