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Open AccessArticle

Iron Causes Lipid Oxidation and Inhibits Proteasome Function in Multiple Myeloma Cells: A Proof of Concept for Novel Combination Therapies

1
Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
2
Fondazione Centro San Raffaele, 20132 Milan, Italy
3
Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
4
Department of Veterinary Sciences, University of Turin, 10095 Grugliasco, Italy
5
School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(4), 970; https://doi.org/10.3390/cancers12040970
Received: 24 December 2019 / Revised: 6 April 2020 / Accepted: 10 April 2020 / Published: 14 April 2020
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 dextran or ferric carboxymaltose to the bortezomib-melphalan-prednisone (VMP) regimen increased the therapeutic response and prolonged remission without causing evident toxicity. We conclude that iron loading interferes both with redox and protein homeostasis, a property that can be exploited to design novel combination strategies including iron supplementation, to increase the efficacy of current MM therapies. View Full-Text
Keywords: multiple myeloma; iron; ferroptosis; proteasome multiple myeloma; iron; ferroptosis; proteasome
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Bordini, J.; Morisi, F.; Cerruti, F.; Cascio, P.; Camaschella, C.; Ghia, P.; Campanella, A. Iron Causes Lipid Oxidation and Inhibits Proteasome Function in Multiple Myeloma Cells: A Proof of Concept for Novel Combination Therapies. Cancers 2020, 12, 970.

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