谷氨酰胺饥饿调控肿瘤线粒体代谢的分子机制

Cancer is one of major threats for health and is the second leading cause of death worldwide. One of the hallmarks of cancer is reprogramming of energy metabolism. To gain a better understanding of the underlying mechanism leading to tumorigenesis is helpful for finding new targets for therapy. The resurgence of research into cancer metabolism has recently broadened our interests from glucose to other nutrients, such as glutamine or serine. Glutamine is essential for proliferation and biosynthesis of many cancer cells, and glutamine starvation has been proven to induce cell growth arrest, autophagy and apoptosis. However, few in-depth studies are reported on the connections between mitochondria functions and glutamine starvation. Based on our preliminary results, we propose that glutamine starvation causes mitochondria respiration dysfunction through protein DDIT3, a stress-response sensor. The goal of this proposal is to investigate how glutamine starvation affects mitochondria functions and characterize its underlying mechanism. We are also interested in delineated the role of DDIT3 in regulating equilibrium between aerobic glycolysis and mitochondrial oxidative phosphorylation.

肿瘤是威胁人类健康最主要疾病之一，在很多国家被称为“第二杀手”。肿瘤的重要特征之一是能量代谢的改变。因此，研究肿瘤细胞代谢对我们寻找治疗肿瘤的对策会有很大帮助。近年来，人们对于肿瘤代谢的兴趣已经从葡萄糖代谢扩展到其他营养物质的代谢上，比如谷氨酰胺代谢或丝氨酸代谢。谷氨酰胺代谢是肿瘤细胞增殖和生物合成所必需的，研究表明：谷氨酰胺饥饿能够诱导肿瘤细胞生长阻滞，诱导自噬以及促进凋亡。然而，谷氨酰胺饥饿和线粒体功能之间的关系还鲜有报道。根据我们前期的研究基础，本项目旨在探究谷氨酰胺饥饿是如何通过所谓“压力响应分子”DDIT3引起线粒体呼吸功能的下降，并阐明其具体的分子机制。另外，本项目也将探索DDIT3如何参与氧化磷酸化和有氧糖酵解之间的平衡。

谷氨酰胺饥饿能够诱导肿瘤细胞生长阻滞，诱导自噬以及促进凋亡。我们通过研究谷氨酰胺饥饿的应激条件下，肿瘤细胞中糖酵解和线粒体中呼吸链代谢的分子机制，在分子、细胞及生理水平上阐明这些代谢的改变如何影响肿瘤的发生发展。我们取得的代表性成果包括：（1）阐明了在谷氨酰胺饥饿的应激条件下，内质网应激蛋白DDIT3促进糖酵解，为肿瘤存活提供足够的ATP，并表明DDIT3通过进入线粒体抑制线粒体氧化磷酸化，减少产生过多的ROS对细胞造成损伤；DDIT3通过这样的双重机制既保证了由糖酵解产生足够的能量，又避免了过多的由线粒体呼吸产生的有害物质ROS，确保肿瘤有效地克服了谷氨酰胺缺失给细胞带来的不利影响。（2）环形RNA CircACC1调控细胞代谢，研究发现了从营养缺乏下的一条JNK-c-JUN-circACC1-AMPK 细胞存活通路。通过这一信号通路，丰富了我们对环形RNA参与细胞代谢调控的认识。相信我们的研究成果将会对人们所预期的用干预代谢的方法预防和治疗肿瘤提供新的理论基础。