Department of Cancer Cell Biology and National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China.
Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, People's Republic of China.
J Exp Med. 2020 Mar 2;217(3). doi: 10.1084/jem.20191226.
Cancer cells often proliferate under hypoxia and reprogram their metabolism. However, how to find targets to effectively block the hypoxia-associated metabolic pathways remains unclear. Here, we developed a tool to conveniently calculate electrons dissipated in metabolic transformations. Based on the law of conservation of electrons in chemical reactions, we further built up an electron balance model for central carbon metabolism, and it can accurately outline metabolic plasticity under hypoxia. Our model specifies that glutamine metabolism reprogrammed for biosynthesis of lipid and/or proline actually acts as the alternative electron bin to enable electron transfer in proliferating cells under hypoxia. Inhibition of both proline biosynthesis and lipogenesis can synergistically suppress cancer cell growth under hypoxia and in vivo tumor onset. Therefore, our model helps to reveal combinations of potential targets to inhibit tumor growth by blocking hypoxia-rewired metabolism and provides a useful tool for future studies on cancer metabolism.
癌细胞在缺氧环境下常常过度增殖并重新编程其代谢。然而，如何找到有效的靶点来阻断与缺氧相关的代谢途径仍不清楚。在这里，我们开发了一种工具，可以方便地计算代谢转化中耗散的电子。基于化学反应中电子守恒定律，我们进一步建立了一个用于中心碳代谢的电子平衡模型，该模型可以准确描绘缺氧下的代谢可塑性。我们的模型指出，谷氨酰胺代谢为脂质和/或脯氨酸的生物合成重新编程实际上充当了替代电子库，以使缺氧环境下增殖细胞中的电子转移成为可能。抑制脯氨酸生物合成和脂肪生成可以协同抑制缺氧条件下和体内肿瘤发生时的癌细胞生长。因此，我们的模型有助于揭示通过阻断缺氧重编代谢来抑制肿瘤生长的潜在靶点组合，并为未来的癌症代谢研究提供了有用的工具。
