Research Papers:

Serum depletion induced cancer stem cell-like phenotype due to nitric oxide synthesis in oncogenic HRas transformed cells

Keisuke Monji, Takeshi Uchiumi _, Saki Hoshizawa, Mikako Yagi, Takashi Matsumoto, Daiki Setoyama, Yuichi Matsushima, Kazuhito Gotoh, Rie Amamoto and Donchon Kang

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Oncotarget. 2016; 7:75221-75234. https://doi.org/10.18632/oncotarget.12117

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Keisuke Monji1, Takeshi Uchiumi1, Saki Hoshizawa1, Mikako Yagi1, Takashi Matsumoto1, Daiki Setoyama1, Yuichi Matsushima1, Kazuhito Gotoh1, Rie Amamoto1,2, Donchon Kang1

1Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan

2Department of Nutritional Sciences, Faculty of Health and Welfare, Seinan Jo Gakuin University, Kokurakita-ku, Kitakyushu 803-0835, Japan

Correspondence to:

Takeshi Uchiumi, email: [email protected]

Keywords: serum depletion, nitric oxide, cancer stem cell, HRas, OXPHOS

Received: May 24, 2016     Accepted: September 02, 2016     Published: September 19, 2016


Cancer cells rewire their metabolism and mitochondrial oxidative phosphorylation (OXPHOS) to promote proliferation and maintenance. Cancer cells use multiple adaptive mechanisms in response to a hypo-nutrient environment. However, little is known about how cancer mitochondria are involved in the ability of these cells to adapt to a hypo-nutrient environment. Oncogenic HRas leads to suppression of the mitochondrial oxygen consumption rate (OCR), but oxygen consumption is essential for tumorigenesis. We found that in oncogenic HRas transformed cells, serum depletion reversibly increased the OCR and membrane potential. Serum depletion promoted a cancer stem cell (CSC)-like phenotype, indicated by an increase in CSC markers expression and resistance to anticancer agents. We also found that nitric oxide (NO) synthesis was significantly induced after serum depletion and that NO donors modified the OCR. An NOS inhibitor, SEITU, inhibited the OCR and CSC gene expression. It also reduced anchorage-independent growth by promoting apoptosis. In summary, our data provide new molecular findings that serum depletion induces NO synthesis and promotes mitochondrial OXPHOS, leading to tumor progression and a CSC phenotype. These results suggest that mitochondrial OCR inhibitors can be used as therapy against CSC.

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