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

• Published in: Oncotarget 2016-11, Vol.7 (46), p.75221-75234
• Main Authors: Monji, Keisuke, Uchiumi, Takeshi, Hoshizawa, Saki, Yagi, Mikako, Matsumoto, Takashi, Setoyama, Daiki, Matsushima, Yuichi, Gotoh, Kazuhito, Amamoto, Rie, Kang, Donchon
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Biomarkers; Cell Cycle Checkpoints - drug effects; Cell Line, Transformed; Cell Line, Tumor; Cell Respiration - genetics; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Disease Models, Animal; Gene Expression; Metformin - pharmacology; Mice; Mice, Knockout; Mitochondria - genetics; Mitochondria - metabolism; Models, Biological; Mutation; Neoplastic Stem Cells - metabolism; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - antagonists & inhibitors; Oxidative Phosphorylation; Phenotype; ras Proteins - genetics; Reactive Oxygen Species - metabolism; Research Paper; Signal Transduction
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.12117

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.