Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth
Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth
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DOI：
10.1016/j.molcel.2015.08.013
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发表时间：
2015-10-15
期刊：
影响因子：
16
通讯作者：
Jones, Russell G.
中科院分区：
文献类型：
--
作者：
Vincent, Emma E.;Sergushichev, Alexey;Jones, Russell G.
癌细胞适应新陈代谢，在营养限制下增殖。在这里，我们使用联合转录-代谢网络分析来确定支持葡萄糖非依赖性肿瘤细胞增殖的代谢途径。我们发现，缺糖刺激了三羧酸(TCA)循环的重新连接和糖异生的早期步骤，以促进葡萄糖非依赖性细胞的增殖。葡萄糖限制可促进谷氨酰胺合成磷酸烯醇式丙酮酸(PEP)，这是通过线粒体PEP-羧基激酶(PCK2)的活性实现的。在这些条件下，谷氨酰胺衍生的PEP被用来为通常由葡萄糖维持的生物合成途径提供燃料，包括丝氨酸和嘌呤的生物合成。PCK2的表达是维持体外有限葡萄糖条件下肿瘤细胞增殖和体内肿瘤生长所必需的。在几种人类肿瘤类型中观察到PCK2表达升高，并在非小细胞肺癌(NSCLC)患者的肿瘤组织中丰富。我们的结果确定了PCK2在癌细胞代谢重编程中的作用，该重编程促进了人类肿瘤中葡萄糖非依赖性细胞的生长和代谢应激抵抗。
Cancer cells adapt metabolically to proliferate under nutrient limitation. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell proliferation. We found that glucose deprivation stimulated re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote glucose-independent cell proliferation. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine via the activity of mitochondrial PEP-carboxykinase (PCK2). Under these conditions, glutamine-derived PEP was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. PCK2 expression was required to maintain tumor cell proliferation under limited-glucose conditions in vitro and tumor growth in vivo. Elevated PCK2 expression is observed in several human tumor types and enriched in tumor tissue from non-small-cell lung cancer (NSCLC) patients. Our results define a role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.