Hodakoski Cindy, Hopkins Benjamin D, Zhang Guoan, Su Taojunfeng, Cheng Zhe, Morris Roxanne, Rhee Kyu Y, Goncalves Marcus D, Cantley Lewis C
Meyer Cancer Center, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY 10021, USA.
Proteomics and Metabolomics Core Facility, Weill Cornell Medicine, New York, NY 10021, USA.
Cancers (Basel). 2019 Jan 2;11(1):37. doi: 10.3390/cancers11010037.
Cancer cells can adapt to nutrient poor conditions by rewiring their metabolism and using alternate fuel sources. Identifying these adaptive metabolic pathways may provide novel targets for cancer therapy. Here, we identify a subset of non-small cell lung cancer (NSCLC) cell lines that survive in the absence of glucose by internalizing and metabolizing extracellular protein via macropinocytosis. Macropinocytosis is increased in these glucose independent cells, and is regulated by phosphoinositide 3-kinase (PI3K) activation of Rac-Pak signaling. Furthermore, inhibition of Rac-dependent macropinocytosis blocks glucose-independent proliferation. We find that degradation of internalized protein produces amino acids, including alanine, which generates TCA cycle and glycolytic intermediates in the absence of glucose. In this process, the conversion of alanine to pyruvate by alanine transaminase 2 (ALT2) is critical for survival during glucose starvation. Collectively, Rac driven macropinocytosis of extracellular protein is an adaptive metabolic pathway used by a subset of lung cancers to survive states of glucose deprivation, and may serve as a potential drug target for cancer therapy.
癌细胞可通过重新连接其代谢过程并利用替代燃料来源来适应营养匮乏的状况。识别这些适应性代谢途径可能为癌症治疗提供新的靶点。在此，我们鉴定出了一部分非小细胞肺癌（NSCLC）细胞系，这些细胞系通过巨胞饮作用内化并代谢细胞外蛋白质，从而在无葡萄糖的情况下存活。在这些不依赖葡萄糖的细胞中，巨胞饮作用增强，且受Rac-Pak信号通路的磷酸肌醇3-激酶（PI3K）激活调控。此外，抑制Rac依赖的巨胞饮作用可阻断不依赖葡萄糖的增殖。我们发现内化蛋白质的降解产生了氨基酸，包括丙氨酸，丙氨酸在无葡萄糖的情况下生成三羧酸循环和糖酵解中间体。在此过程中，丙氨酸转氨酶2（ALT2）将丙氨酸转化为丙酮酸对于葡萄糖饥饿期间的存活至关重要。总体而言，Rac驱动的细胞外蛋白质巨胞饮作用是一部分肺癌用于在葡萄糖剥夺状态下存活的适应性代谢途径，并且可能作为癌症治疗的潜在药物靶点。
