Oncotarget

Research Papers:

Alteration of mitochondrial biogenesis promotes disease progression in multiple myeloma

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

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Oncotarget. 2017; 8:111213-111224. https://doi.org/10.18632/oncotarget.22740

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Abstract

Xin Zhan1,*, Wenjie Yu2,*, Reinaldo Franqui-Machin1,3, Melissa L. Bates4, Kalyan Nadiminti1, Huojun Cao5, Brad A. Amendt2,5, Yogesh Jethava1, Ivana Frech1, Fenghuang Zhan1 and Guido Tricot1

1Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA

2Department of Anatomy and Cell Biology University of Iowa, Iowa City, IA, USA

3Molecular & Cellular Biology Program, University of Iowa, Iowa City, IA, USA

4Department of Health and Human Physiology, University of Iowa, Iowa City, IA, USA

5Department 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.


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