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.

中文翻译：

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谷氨酰胺剥夺抵消了低氧诱导的化学抗性。

实体瘤的微环境是治疗功效的关键决定因素。氧气和养分剥夺的共同存在是肿瘤微环境的普遍现象，并与治疗抵抗有关。胆管癌（CCA）的特点是预后很差，化学抵抗力明显。迫切需要更好地了解潜在的分子机制，以改善针对CCA的治疗策略。我们试图研究有条件必需氨基酸谷氨酰胺（CCA）的重要性，谷氨酰胺是多种实体瘤的重要营养物质。在CCA样品中，谷氨酰胺水平大大降低，建立的人CCA细胞系的生长高度依赖于谷氨酰胺。通过逐渐减少外部谷氨酰胺，我们生成了CCA细胞系的衍生物，这些衍生物能够在没有外部谷氨酰胺（称为谷氨酰胺耗竭（GD））的情况下生长。为了分析同时缺氧和谷氨酰胺剥夺的影响，在常氧和低氧下用顺铂或吉西他滨处理GD细胞。令人惊讶的是，在GD细胞中，完全建立的低氧诱导的化学抗性现象被完全逆转。为了更好地理解其潜在机制，我们集中于癌基因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。相反，响应于GD细胞中的组合治疗，c-Myc表达降低，表明c-Myc在低氧诱导的化学抗性过程中的功能重要性。总之，