苹果酸酶调控肿瘤细胞命运的分子机制研究

肿瘤细胞往往会异常改变一些重要的代谢方式以快速或大量获得所需的能量和各种中间代谢产物用于生物合成，及遏制由快速生物合成带来的活性氧的产生和积累，并维持有利于生长、存活的细胞内外环境。代谢的异常改变通常与肿瘤蛋白或其通路的突变密切相关。Myc是肿瘤发生、发展过程中具有重要调控作用的蛋白。Myc信号通路的改变显著影响了能量代谢过程，甚至导致细胞对营养物质的极大依赖。但是，Myc调控肿瘤代谢异常的机制仍在不断探索中。申请人近期的研究发现，苹果酸酶代谢的异常改变显著增强了肿瘤细胞内的生物合成。但是，目前对于苹果酸酶代谢调控的研究知之甚少。因此，该项目拟从Myc介导的谷氨酰胺代谢入手，研究苹果酸酶在Myc高表达细胞内的生物学功能，并阐明其确切的分子机制。相信通过该项研究，将使人们深入了解苹果酸酶和Myc在肿瘤代谢和细胞命运决定过程中的调控作用和机制；在临床上，有望为抗癌药物的设计提供新的思路和靶点。

Nutrient metabolism is markedly reprogrammed in cancer cells to meet their high demand of biogenesis for cell proliferation or survival. It has been increasing clear that metabolic alteration is regulated by signaling transduction changes, leading to buildup of ATP and numerous metabolites, which are crucial for biosynthesis and detoxification of reactive oxygen species (ROS). Tumor protein Myc plays a key role in tumorigenesis and glutaminolysis. We previously found that the TCA-associated malic enzyme pathway is key to biosynthesis and tumor growth. However, the mechanisms for both Myc and malic enzymes (MEs) in tumor metabolism are not well understood. Here, based on our previous and recent findings, we will: 1) determine whether and how Myc regulates MEs expression; 2), define the role of MEs in Myc-mediated glutamine metabolism, cellular adaptation to glutamine deprivation, and tumor growth. The overall objective of this research proposal is to reveal previously unrecognized interplays between MEs and Myc in tumor metabolism and cell fate decision, and may provide a rationale for anti-cancer drug development.