Oncotarget

Research Papers:

The iron chelator deferasirox induces apoptosis by targeting oncogenic Pyk2/β-catenin signaling in human multiple myeloma

Yusuke Kamihara _, Kohichi Takada, Tsutomu Sato, Yutaka Kawano, Kazuyuki Murase, Yohei Arihara, Shohei Kikuchi, Naotaka Hayasaka, Makoto Usami, Satoshi Iyama, Koji Miyanishi, Yasushi Sato, Masayoshi Kobune and Junji Kato

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Oncotarget. 2016; 7:64330-64341. https://doi.org/10.18632/oncotarget.11830

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Abstract

Yusuke Kamihara1,*, Kohichi Takada1,*, Tsutomu Sato1, Yutaka Kawano1, Kazuyuki Murase1, Yohei Arihara1, Shohei Kikuchi1, Naotaka Hayasaka1, Makoto Usami1, Satoshi Iyama1, Koji Miyanishi1, Yasushi Sato1, Masayoshi Kobune1, Junji Kato1

1Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Japan

*These authors have contributed equally to this work

Correspondence to:

Junji Kato, email: [email protected]

Keywords: deferasirox, Pyk2, β-catenin, apoptosis, multiple myeloma

Received: October 06, 2015    Accepted: August 21, 2016    Published: September 02, 2016

ABSTRACT

Deregulated iron metabolism underlies the pathogenesis of many human cancers. Recently, low expression of ferroportin, which is the only identified non-heme iron exporter, has been associated with significantly reduced overall survival in multiple myeloma (MM); however, the altered iron metabolism in MM biology remains unclear. In this study we demonstrated, by live cell imaging, that MM cells have increased intracellular iron levels as compared with normal cells. In experiments to test the effect of iron chelation on the growth of MM cells, we found that deferasirox (DFX), an oral iron chelator used to treat iron overload in clinical practice, inhibits MM cell growth both in vivo and in vitro. Mechanistically, DFX was found to induce apoptosis of MM cells via the inhibition of proline-rich tyrosine kinase 2 (Pyk2), which is known to promote tumor growth in MM. Inhibition of Pyk2 is caused by the suppression of reactive oxygen species, and leads to downregulation of the Wnt/β-catenin signaling pathway. Taken together, our findings indicate that high levels of intracellular iron, which might be due to low ferroportin expression, play a role in MM pathophysiology. Therefore, DFX may provide a therapeutic option for MM that is driven by deregulated iron homeostasis and/or Pyk2/Wnt signaling.


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