Glutamine deprivation counteracts hypoxia-induced chemoresistance
Glutamine deprivation counteracts hypoxia-induced chemoresistance
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DOI：
10.1016/j.neo.2019.10.004
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发表时间：
2019-11
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影响因子：
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通讯作者：
Jessica Wappler;Martijn Arts;A. Röth;R. Heeren;Ulf Peter Neumann;S. O. Olde Damink;Z. Soons;T. Cramer
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文献类型：
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作者：
Jessica Wappler;Martijn Arts;A. Röth;R. Heeren;Ulf Peter Neumann;S. O. Olde Damink;Z. Soons;T. Cramer
实体瘤的微环境是治疗效果的关键决定因素。氧和营养缺乏的共同发生是肿瘤微环境的常见现象，并与治疗抵抗相关。胆管癌（CCA）的特点是预后非常差和明显的化疗耐药性。更好地了解潜在的分子机制是迫切需要改善治疗策略对CCA。我们试图研究条件必需氨基酸谷氨酰胺对CCA的重要性，谷氨酰胺是各种实体瘤的重要营养素。谷氨酰胺水平在CCA样品中强烈降低，并且建立的人CCA细胞系的生长高度依赖于谷氨酰胺。使用逐渐减少的外部谷氨酰胺，我们产生的CCA细胞系的衍生物，能够生长没有外部谷氨酰胺（称为谷氨酰胺耗尽（GD））。为了分析同时缺氧和谷氨酰胺剥夺的影响，GD细胞在常氧和缺氧下用顺铂或吉西他滨处理。引人注目的是，缺氧诱导的化疗耐药的良好现象在GD细胞中被完全逆转。为了更好地了解潜在的机制，我们专注于癌基因c-Myc。顺铂和缺氧的组合导致野生型细胞中持续的c-Myc蛋白表达。与此相反，c-Myc的表达减少，在GD细胞的组合治疗，表明在缺氧诱导的化学抗性的过程中的c-Myc的功能的重要性。总之，这些发现表明，驱动适应肿瘤微环境变化的机制及其与治疗反应的相关性比预期的更复杂。
The microenvironment of solid tumors is a key determinant of therapy efficacy. The co-occurrence of oxygen and nutrient deprivation is a common phenomenon of the tumor microenvironment and associated with treatment resistance. Cholangiocarcinoma (CCA) is characterized by a very poor prognosis and pronounced chemoresistance. A better understanding of the underlying molecular mechanisms is urgently needed to improve therapy strategies against CCA. We sought to investigate the importance of the conditionally essential amino acid glutamine, a centrally important nutrient for a variety of solid tumors, for CCA. Glutamine levels were strongly decreased in CCA samples and the growth of established human CCA cell lines was highly dependent on glutamine. Using gradual reduction of external glutamine, we generated derivatives of CCA cell lines which were able to grow without external glutamine (termed glutamine-depleted (GD)). To analyze the effects of coincident oxygen and glutamine deprivation, GD cells were treated with cisplatin or gemcitabine under normoxia and hypoxia. Strikingly, the well-established phenomenon of hypoxia-induced chemoresistance was completely reversed in GD cells. In order to better understand the underlying mechanisms, we focused on the oncogene c-Myc. The combination of cisplatin and hypoxia led to sustained c-Myc protein expression in wildtype cells. In contrast, c-Myc expression was reduced in response to the combinatorial treatment in GD cells, suggesting a functional importance of c-Myc in the process of hypoxia-induced chemoresistance. In summary, these findings indicate that the mechanisms driving adaption to tumor microenvironmental changes and their relevance for the response to therapy are more complex than expected.