Hypoxia-inducible factor-1α promotes cell survival during ammonia stress response in ovarian cancer stem-like cells.
Hypoxia-inducible factor-1α promotes cell survival during ammonia stress response in ovarian cancer stem-like cells.
复制标题
低氧诱导因子1α促进卵巢癌干细胞中氨胁迫反应期间的细胞存活。
DOI：
10.18632/oncotarget.23010
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发表时间：
2017-12-29
期刊：
影响因子：
--
通讯作者：
Poellinger L
中科院分区：
文献类型：
--
作者：
Kitajima S;Lee KL;Hikasa H;Sun W;Huang RY;Yang H;Matsunaga S;Yamaguchi T;Araki M;Kato H;Poellinger L
氨是一种有毒的代谢副产品，会导致细胞应激。虽然许多蛋白质参与适应性应激反应，但对抗氨诱导的细胞应激并调节细胞代谢以抵抗其毒性的特定因子尚未被确定。我们证明了缺氧诱导因子-1 α（HIF-1α）在氨应激下是稳定和激活的。氯化铵激活的HIF-1α抑制氨诱导的细胞凋亡此外，我们确定了谷氨酰胺合成酶（GS）作为氨应激下癌细胞增殖的关键驱动因素，以及表达CD 90的卵巢癌干细胞样细胞中谷氨酰胺依赖性代谢。有趣的是，活化的HIF-1α通过促进糖酵解和提高葡萄糖依赖性来抵消谷氨酰胺合成酶在谷氨酰胺代谢中的功能。我们的研究揭示了HIF-1α在癌症干细胞样细胞中的双相氨应激管理中迄今未知的功能，其中GS促进细胞增殖，HIF-1α有助于能量燃料使用中的代谢重塑，导致增殖减弱，但反过来促进细胞存活。
Ammonia is a toxic by-product of metabolism that causes cellular stresses. Although a number of proteins are involved in adaptive stress response, specific factors that counteract ammonia-induced cellular stress and regulate cell metabolism to survive against its toxicity have yet to be identified. We demonstrated that the hypoxia-inducible factor-1α (HIF-1α) is stabilized and activated by ammonia stress. HIF-1α activated by ammonium chloride compromises ammonia-induced apoptosis. Furthermore, we identified glutamine synthetase (GS) as a key driver of cancer cell proliferation under ammonia stress and glutamine-dependent metabolism in ovarian cancer stem-like cells expressing CD90. Interestingly, activated HIF-1α counteracts glutamine synthetase function in glutamine metabolism by facilitating glycolysis and elevating glucose dependency. Our studies reveal the hitherto unknown functions of HIF-1α in a biphasic ammonia stress management in the cancer stem-like cells where GS facilitates cell proliferation and HIF-1α contributes to the metabolic remodeling in energy fuel usage resulting in attenuated proliferation but conversely promoting cell survival.
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