Cancer cells exhibit metabolic dependence on mitochondrial glutamine metabolism that provides them with the substrates required for rapid proliferation. Despite the extensive efforts to target this glutamine addiction for therapeutic purposes, the adaptive metabolic responses and the mechanisms whereby cells maintain their unlimited growth remain areas of active investigation. Here we report that mitochondrial glutamate-pyruvate transaminase 2 (GPT2) contributes to cell survival and growth by sustaining the tricarboxylic acid (TCA) cycle anaplerosis after the inhibition of glutaminase (GLS), the first enzyme for mitochondrial glutamine metabolism. We found that elevated reactive oxygen species upon GLS inhibition induce GPT2 expression via activating transcription factor 4. Moreover, inhibition of GPT2 synergized with suppression of GLS activity to induce a pronounced reduction in proliferation and an increase in cell death of cancer cells. Our data uncover GPT2 as an important component of the adaptive metabolic response for glutamine deprivation and indicate that targeting this pathway in combination with GLS inhibition may be an effective therapeutic approach for cancer treatment.

中文翻译：

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线粒体GPT2在对线粒体谷氨酰胺代谢扰动的代谢适应中起关键作用。

癌细胞表现出对线粒体谷氨酰胺代谢的代谢依赖性，从而为癌细胞提供了快速增殖所需的底物。尽管为了治疗目的针对这种谷氨酰胺成瘾进行了广泛的努力，但是适应性代谢反应和细胞维持其无限生长的机制仍然是积极研究的领域。在这里，我们报道线粒体谷氨酸-丙酮酸转氨酶2（GPT2）通过抑制谷氨酸酶（GLS）（线粒体谷氨酰胺代谢的第一种酶）后维持三羧酸（TCA）周期的动脉硬化来促进细胞存活和生长。我们发现，经GLS抑制后，活性氧含量升高，可通过激活转录因子4诱导GPT2表达。抑制GPT2与抑制GLS活性协同作用，从而诱导癌细胞的增殖明显减少和细胞死亡增加。我们的数据揭示了GPT2是谷氨酰胺剥夺适应性代谢反应的重要组成部分，并表明与GLS抑制结合靶向该途径可能是一种有效的癌症治疗方法。