抗肿瘤谷氨酰胺转运靶点SLC1A5的分子调控机制研究及靶向药物筛选

Elevated glutamine metabolism is an essential feature of malignant transformation. Regardless of their origin, tumor cells constantly require a large amount of glutamine supply to support their characteristic unabated growth. We and others have reported that tumor cells frequently overexpress SLC1A5, and highly depend on SLC1A5 activity for glutamine transport. However, molecular mechanisms of SLC1A5 upregulation and subsequently its physilogical significance in tumor maintenance are largely unknown. Combining approaches of molecular cell biology, biochemistry and animal modeling, we aim to 1) study the mechanisms whereby tumor cells activates SLC1A5 overexpression; 2) functionally analyze SLC1A5 in animal models to confirm its roles in tumor maintenance; and 3) test the tumor suppressive activity of the candidate compounds capable of inhibiting SLC1A5 function. The overarching goal of these studies is to gain insight into the molecular mechanisms of SLC1A5 regulation and to evaluate the feasibility and efficacy of targeting SLC1A5 in cancer therapy. Furthermore, the studies will direct toward the identification of small molecules or other bioactive agents to modulate tumor glutamine metabolism with a view toward therapeutic applications.

独特的谷氨酰胺代谢是肿瘤细胞区别于正常细胞的本质特征。肿瘤细胞高度依赖转运蛋白SLC1A5[solute carrier family 1 (neutral amino acid transporter), member 5]提供其生长所必需的谷氨酰胺。SLC1A5在肿瘤细胞中过量表达,然而关于SLC1A5基因表达的调控机制及其在肿瘤发展过程中的生物学作用，尚未完全清楚。基于前期工作，本课题拟采用分子细胞生物学、生物化学、模式动物等学科交叉的研究方法，进一步（1）研究肿瘤细胞过表达SLC1A5的分子机制；（2）探讨SLC1A5在维持肿瘤生长过程中的生物学作用；（3）检测SLC1A5专一抑制剂的抗肿瘤活性。本项目可望阐明SLC1A5的调控机制及生物学作用，明确SLC1A5作为新型治疗靶点的可行性，获得专一性抑制SLC1A5的先导化合物，以期为抗癌新药的研发和癌症的有效治疗提供前期基础。

肿瘤细胞高度依赖谷氨酰胺为其生长提供原料物质。然而，谷氨酰胺转运的分子调控机制及其在肿瘤发展过程中的作用尚未明确。本项目旨在探讨谷氨酰胺转运体SLC1A5（亦称ASCT2）的调控机制及其通过代谢重编程调节肿瘤发生发展的病理机制，重点研究以下三方面的内容：（1）应激因子ATF4和抑癌micRNA-137调控ASCT2的分子机制及生物学意义；（2）热休克蛋白HSP90-Notch1通路调控ASCT2和谷氨酰胺代谢促白血病发展的分子机制；（3）ASCT2抑制剂通过代谢重编程诱导肿瘤细胞死亡的分子机制。通过以上三方面深入研究，申请人取得了很好的进展，并以通讯作者身份在主流期刊发表研究论文5篇，包括1篇Clinical Cancer Research, 1篇The Journal of Pathology，2篇Oncogene 和1篇Oncogenesis。这些研究不仅系统阐述了ASCT2的分子调控新机制，而且为旨在以ASCT2为靶点的肿瘤靶向治疗提供了科学依据。