Glutamine activates STAT3 to control cancer cell proliferation independently of glutamine metabolism.
Glutamine activates STAT3 to control cancer cell proliferation independently of glutamine metabolism.
复制标题
谷氨酰胺激活 STAT3 以独立于谷氨酰胺代谢控制癌细胞增殖。
DOI：
10.1038/onc.2016.364
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发表时间：
2017-04
期刊：
影响因子：
8
通讯作者：
Sonveaux P
中科院分区：
文献类型：
--
作者：
Cacace A;Sboarina M;Vazeille T;Sonveaux P
癌细胞可以使用多种代谢底物来满足其致癌程序的生物能量和生物合成需求。除了生物能量学，癌细胞代谢还直接影响与肿瘤进展相关的遗传、表观遗传和信号传导事件。许多癌细胞对谷氨酰胺成瘾，并且在氧化细胞和糖酵解细胞中观察到这种成瘾。虽然氧化和生物还原谷氨酰胺代谢可以促进癌症的进展，谷氨酰胺可以进一步产生肽（包括谷胱甘肽）和蛋白质，我们报告说，谷氨酰胺促进癌细胞的增殖独立于其作为代谢燃料或作为谷胱甘肽的前体。细胞外谷氨酰胺激活转录因子STAT 3，这是必要的，足以介导谷氨酰胺在糖酵解和氧化癌细胞中的增殖作用。谷氨酰胺还激活转录因子HIF-1、mTOR和c-Myc，但这些因子不介导谷氨酰胺对癌细胞增殖的影响。我们的研究结果为L-天冬酰胺酶的抗癌作用提供了新的线索，L-天冬酰胺酶具有谷氨酰胺酶活性，并在细胞外将谷氨酰胺转化为谷氨酸。相反，癌症对阻断谷氨酰胺代谢的治疗的抗性可能来自谷氨酰胺非依赖性STAT 3再激活。
Cancer cells can use a variety of metabolic substrates to fulfill the bioenergetic and biosynthetic needs of their oncogenic program. Besides bioenergetics, cancer cell metabolism also directly influences genetic, epigenetic and signaling events associated with tumor progression. Many cancer cells are addicted to glutamine, and this addiction is observed in oxidative as well as in glycolytic cells. While both oxidative and bioreductive glutamine metabolism can contribute to cancer progression and glutamine can further serve to generate peptides (including glutathione) and proteins, we report that glutamine promotes the proliferation of cancer cells independently of its use as a metabolic fuel or as a precursor of glutathione. Extracellular glutamine activates transcription factor STAT3, which is necessary and sufficient to mediate the proliferative effects of glutamine in glycolytic and in oxidative cancer cells. Glutamine also activates transcription factors HIF-1, mTOR and c-Myc, but these factors do not mediate the effects of glutamine on cancer cell proliferation. Our findings shed a new light on the anticancer effects of L-asparaginase that possesses glutaminase activity and converts glutamine into glutamate extracellularly. Conversely, cancer resistance to treatments that block glutamine metabolism could arise from glutamine-independent STAT3 re-activation.