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Iron Causes Lipid Oxidation and Inhibits Proteasome Function in Multiple Myeloma Cells: A Proof of Concept for Novel Combination Therapies by Bordini, Jessica; Morisi, Federica; Cerruti, Fulvia; Cascio, Paolo; Camaschella, Clara; Ghia, Paolo; Campanella, Alessandro is a Medicine article available to read on EtoBox.

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Adaptation to import iron for proliferation makes cancer cells potentially sensitive to iron toxicity. Iron loading impairs multiple myeloma (MM) cell proliferation and increases the efficacy of the proteasome inhibitor bortezomib. Here, we defined the mechanisms of iron toxicity in MM.1S, U266, H929, and OPM-2 MM cell lines, and validated this strategy in preclinical studies using Vk\*MYC mice as MM model. High-dose ferric ammonium citrate triggered cell death in all cell lines tested, increasing malondialdehyde levels, the by-product of lipid peroxidation and index of ferroptosis. In addition, iron exposure caused dose-dependent accumulation of polyubiquitinated proteins in highly iron-sensitive MM.1S and H929 cells, suggesting that proteasome workload contributes to iron sensitivity. Accordingly, high iron concentrations inhibited the proteasomal chymotrypsin-like activity of 26S particles and of MM cellular extracts in vitro. In all MM cells, bortezomib-iron combination induced persistent lipid damage, exacerbated bortezomib-induced polyubiquitinated proteins accumulation, and triggered cell death more efficiently than individual treatments. In Vk\*MYC mice, addition of iron de

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Author

Bordini, Jessica; Morisi, Federica; Cerruti, Fulvia; Cascio, Paolo; Camaschella, Clara; Ghia, Paolo; Campanella, Alessandro

Publisher

MDPI AG; Multidisciplinary Digital Publishing Institute (MDPI); Basel: MDPI, 2009- (ISSN 2072-6694)

Published

2020

Language

EN

Field

Medicine (Health Sciences)