Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
ITMO University, Saint Petersburg 197101, Russia; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, USA.
Mol Cell. 2015 Oct 15;60(2):195-207. doi: 10.1016/j.molcel.2015.08.013.
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.
癌细胞通过代谢适应在营养限制下增殖。在这里，我们使用联合转录组代谢组网络分析来鉴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，葡萄糖剥夺刺激三羧酸 (TCA) 循环和糖异生早期步骤的重新布线，以促进葡萄糖非依赖性细胞增殖。葡萄糖限制促进了通过线粒体磷酸烯醇丙酮酸羧激酶 (PCK2) 的活性从谷氨酰胺产生磷酸烯醇丙酮酸 (PEP)。在这些条件下，谷氨酰胺衍生的 PEP 用于为通常由葡萄糖维持的生物合成途径提供燃料，包括丝氨酸和嘌呤生物合成。在体外有限葡萄糖条件下和体内肿瘤生长中，PCK2 表达对于维持肿瘤细胞增殖是必需的。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) 患者的肿瘤组织中富集。我们的研究结果定义了 PCK2 在促进人类肿瘤中葡萄糖非依赖性细胞生长和代谢应激抗性的癌细胞代谢重编程中的作用。
