mTORC1/2调控肝癌ARK5介导的谷氨酰胺代谢的作用及机制研究

Receptor of mammalian target of rapamycin (mTOR) inhibitors brought hope to the therapy of hepatocellular carcinoma (HCC). However, traditional mTOR inhibitors only affect the activity of mTOR complex 1(mTORC1), which limited their anti-tumor effects. OSI-027, a novel ATP-competitive inhibitor of mTOR, inhibits both components of the mTOR complex and abrogates hyperactivation of AKT induced by mTORC1 inhibition, has demonstrated potent anticancer effect in HCC. Interestingly, the sensitivities of HCC cells to OSI-027 varied from cell lines, but the mechanism remains unknown. Previous studies have found that the sensitivities of HCC cells to OSI-027 were closed related to the expression level of ARK5, who has been proved to be the key regulator of glutaminolysis in cancer cells. On the other hand, mTOR pathway is also involved in the regulation of glutaminolysis in tumor and normal cells. Based on these indications, present study will explore the role of mTORC1/2 in ARK5 mediated glutaminolysis in HCC, and how ARK5 levels affect the sensitivities of HCC cells to the dual mTORC1/2 inhibitor by various molecular biology experiments. Our results will provide not only a new theoretical basis but also a therapeutic target for further HCC treatment in clinic.

哺乳动物雷帕霉素受体（mTOR）抑制剂的出现为肝细胞肝癌的治疗带来了希望，然而传统的mTOR抑制剂仅抑制mTORC1活性，抗肿瘤疗效有限。OSI-027同时抑制mTORC1和mTORC2复合物活性，有效阻断前者受抑引起的AKT反馈性激活，增强对肝癌的杀伤作用。但不同肝癌细胞对OSI-027的敏感性相差较大，其机制并不清楚。我们前期研究发现，肝癌细胞对OSI-027的敏感性与ARK5表达水平密切相关，而后者是调控肿瘤细胞谷氨酰胺代谢的关键分子；同时，mTOR亦参与谷氨酰胺代谢的调控。故本课题拟以肝癌谷氨酰胺代谢为切入点，应用多种分子生物学技术探索mTOR对ARK5介导的肝癌谷氨酰胺代谢的调控机制,明确ARK5表达水平与肝癌对OSI-027敏感性的关系。研究结果不仅可以为以谷氨酰胺代谢为靶标的肝癌防治策略提供依据，更有望以ARK5为靶点筛选对mTORC1/2抑制剂敏感的肿瘤患者，实现临床转化。