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Alteration of mitochondrial biogenesis promotes disease progression in multiple myeloma

2017; Impact Journals LLC; Volume: 8; Issue: 67 Linguagem: Inglês

10.18632/oncotarget.22740

1949-2553

Xin Zhan, Wenjie Yu, Reinaldo Franqui-Machin, Melissa L. Bates, Kalyan Nadiminti, Huojun Cao, Brad A. Amendt, Yogesh Jethava, Ivana Frech, Fenghuang Zhan, Guido Tricot,

Ubiquitin and proteasome pathways

// Xin Zhan 1, * , Wenjie Yu 2, * , Reinaldo Franqui-Machin 1, 3 , Melissa L. Bates 4 , Kalyan Nadiminti 1 , Huojun Cao 5 , Brad A. Amendt 2, 5 , Yogesh Jethava 1 , Ivana Frech 1 , Fenghuang Zhan 1 and Guido Tricot 1 1 Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA 2 Department of Anatomy and Cell Biology University of Iowa, Iowa City, IA, USA 3 Molecular & Cellular Biology Program, University of Iowa, Iowa City, IA, USA 4 Department of Health and Human Physiology, University of Iowa, Iowa City, IA, USA 5 Department of Endodontics University of Iowa, Iowa City, IA, USA * These authors have contributed equally to this work Correspondence to: Fenghuang Zhan, email: fenghuang-zhan@uiowa.edu Keywords: multiple myeloma; mitochondria biogenesis; iron; disease progression Received: August 24, 2017 Accepted: October 13, 2017 Published: November 27, 2017 ABSTRACT Many cancers, including multiple myeloma (MM), retain more cytosolic iron to promote tumor cell growth and drug resistance. Higher cytosolic iron promotes oxidative damage due to its interaction with reactive oxygen species generated by mitochondria. The variation of mitochondrial biogenesis in different stages of MM disease was evaluated using gene expression profiles in a large clinical dataset. Sixteen of 18mitochondrial biogenesis related gene sets, including mitochondrial biogenesis signature and oxidative phosphorylation, were increased in myeloma cells compared with normal plasma cells and high expression was associated with an inferior patient outcome. Relapsed and drug resistant myeloma samples had higher expression of mitochondrial biogenesis signatures than newly diagnosed patient samples. The expression of mitochondrial biogenesis genes was regulated by the cellular iron content, which showed a synergistic effect in patient outcome in MM. Pharmacological ascorbic acid induced myeloma cell death by inhibition of mitochondria oxidative phosphorylation in an in vivo model. Here, we identify that dysregulated mitochondrial biogenesis and iron homeostasis play a major role in myeloma progression and patient outcome and that pharmacological ascorbic acid, through cellular iron content and mitochondrial oxidative species, should be considered as a novel treatment in myeloma including drug-resistant and relapsed patients.