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 Gotou, Rie Amamoto, Dongchon Kang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)75221-75234
Number of pages14
JournalOncotarget
Volume7
Issue number46
DOIs
Publication statusPublished - Jan 1 2016

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Neoplastic Stem Cells
Oxygen Consumption
Nitric Oxide
Phenotype
Serum
Oxidative Phosphorylation
Neoplasms
Food
Nitric Oxide Donors
Antineoplastic Agents
Membrane Potentials
Mitochondria
Carcinogenesis
Maintenance
Apoptosis
Gene Expression
Growth

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Serum depletion induced cancer stem cell-like phenotype due to nitric oxide synthesis in oncogenic HRas transformed cells. / Monji, Keisuke; Uchiumi, Takeshi; Hoshizawa, Saki; Yagi, Mikako; Matsumoto, Takashi; Setoyama, Daiki; Matsushima, Yuichi; Gotou, Kazuhito; Amamoto, Rie; Kang, Dongchon.

In: Oncotarget, Vol. 7, No. 46, 01.01.2016, p. 75221-75234.

Research output: Contribution to journalArticle

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AU - Matsumoto, Takashi

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