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Research Papers:

Iron depletion is a novel therapeutic strategy to target cancer stem cells

Takayuki Ninomiya, Toshiaki Ohara _, Kazuhiro Noma, Yuki Katsura, Ryoichi Katsube, Hajime Kashima, Takuya Kato, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Ling Chen, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa and Toshiyoshi Fujiwara

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Oncotarget. 2017; 8:98405-98416. https://doi.org/10.18632/oncotarget.21846

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Abstract

Takayuki Ninomiya1, Toshiaki Ohara1,2, Kazuhiro Noma1, Yuki Katsura1, Ryoichi Katsube1, Hajime Kashima1, Takuya Kato1, Yasuko Tomono3, Hiroshi Tazawa1,4, Shunsuke Kagawa1, Yasuhiro Shirakawa1, Fumiaki Kimura5, Ling Chen6,7, Tomonari Kasai6, Masaharu Seno6, Akihiro Matsukawa2 and Toshiyoshi Fujiwara1

1Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

2Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

3Shigei Medical Research Institute, Okayama, Japan

4Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan

5Department of Internal Medicine, Tamano General Hospital, Okayama, Japan

6Department of Medical and Bioengineering Science, Okayama University Graduate School of Natural Science and Technology, Okayama, Japan

7Department of Pathology, Tiajin Central Hospital of Gynecology Obstetrics, Tianjin, People’s Republic of China

Correspondence to:

Toshiaki Ohara, email: t_ohara@cc.okayama-u.ac.jp

Keywords: cancer stem cells, induced pluripotent stem cells, iron chelators, stemness

Received: May 16, 2017     Accepted: September 23, 2017     Published: October 12, 2017

ABSTRACT

Adequate iron levels are essential for human health. However, iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, iron depletion by the iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and iron depletion may be a novel therapeutic strategy to target CSCs.


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