氧化还原信号调控与肿瘤代谢

代谢异常是肿瘤细胞的十大特征之一，肿瘤细胞能够通过代谢重编程满足其快速增殖的物质和能量需求。肿瘤代谢重编程伴随活性氧（reactive oxygen species，ROS）的产生以及抗氧化体系的激活。ROS含量过高会导致氧化损伤甚至细胞死亡，而适量水平的ROS可作为第二信使参与调控多种信号通路。近年来，随着对氧化应激研究的不断深入，发现ROS可直接介导蛋白质发生氧化还原修饰（redox modifications），从而造成蛋白质构象或功能的改变。然而，目前仅报道了3-磷酸甘油醛脱氢酶（glyceraldehyde-3-phosphate dehydrogenase，GAPDH）、M2型丙酮酸激酶（PKM2）等个别代谢酶的氧化还原修饰，其他代谢酶是否受到氧化还原修饰调控并发挥重要功能尚不清楚，靶向代谢酶氧化还原修饰的时空特异性和代偿适应性也是目前的重点和难点。本文将从肿瘤代谢的角度出发，综述近年来报道的有关代谢酶的氧化还原修饰模式、调控机制及其在肿瘤发生发展中的作用，探讨和展望靶向代谢酶氧化还原修饰的肿瘤治疗策略。

A Review of the Redox Regulation of Tumor Metabolism

Metabolic aberrance is one of the hallmarks of cancer. The metabolic patterns in cancer cells are well reprogrammed to provide building blocks and energy for their sustained growth. During tumor metabolic reprogramming, reactive oxygen species (ROS) are generated and the antioxidant systems are activated. High levels of ROS lead to oxidative damage and even cell death, whereas ROS at low levels act as second messenger to regulate many signaling pathways. Recently, with the revisiting of oxidative stress, it has been found that ROS can directly mediate the redox modifications of proteins, resulting in protein conformational and functional alterations. However, only a very small portion of metabolic enzymes, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and PKM2, etc., has been reported to undergo redox modifications. Whether other metabolic enzymes are regulated by redox modifications and thus exhibit critical functions remain largely unknown. Moreover, the specific spatio-temporal targeting of redox modifications of metabolic enzymes, as well as overcoming the existed redox and metabolic adaptation, are key points to be solved. Here, we will review the reported redox modification patterns of metabolic enzymes, the involved regulatory mechanisms and their roles in tumorigenesis and tumor progress. In addition, we will discuss the future therapeutic strategies targeting redox modifications of metabolic enzymes for tumor treatment.