Serum depletion induced cancer stem cell-like phenotype due to nitric oxide synthesis in oncogenic HRas transformed cells.
Serum depletion induced cancer stem cell-like phenotype due to nitric oxide synthesis in oncogenic HRas transformed cells.
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DOI：
10.18632/oncotarget.12117
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发表时间：
2016-11-15
期刊：
影响因子：
--
通讯作者：
Kang D
中科院分区：
文献类型：
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作者：
Monji K;Uchiumi T;Hoshizawa S;Yagi M;Matsumoto T;Setoyama D;Matsushima Y;Gotoh K;Amamoto R;Kang D
癌细胞重新调整其代谢和线粒体氧化磷酸化（OXPHOS）以促进增殖和维持。癌细胞使用多种适应机制来应对低营养环境。然而，人们对癌症线粒体如何参与这些细胞适应低营养环境的能力知之甚少。致癌HRas导致线粒体耗氧率（OCR）的抑制，但耗氧是肿瘤发生所必需的。我们发现，在致癌HRas转化细胞，血清消耗可逆地增加OCR和膜电位。血清耗竭促进了癌症干细胞（CSC）样表型，表明CSC标志物表达增加和对抗癌药物的耐药性。我们还发现，一氧化氮（NO）的合成显着诱导血清耗竭后，NO供体修改OCR。NOS抑制剂SEITU抑制OCR和CSC基因表达。它还通过促进细胞凋亡来减少锚定非依赖性生长。总之，我们的数据提供了新的分子发现，即血清耗竭诱导NO合成并促进线粒体OXPHOS，导致肿瘤进展和CSC表型。这些结果表明，线粒体OCR抑制剂可用作针对CSC的疗法。
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.