PCK1介导丝氨酸代谢重编程在肝癌干细胞化疗耐药中的作用及机理研究

化疗作为肿瘤治疗最为常用的方法之一，对肝癌的有效率却不足20%。积极探索化疗耐药机理和寻找有效干预措施对于肝癌治疗十分重要。我们前期研究发现肝癌组织中糖异生的限速酶磷酸烯醇式丙酮酸羧化激酶（PEPCK）低表达，但在肝癌干细胞中PEPCK的胞浆型PCK1表达却上升，然而升高的PCK1并不能增强糖异生活动，反而促进糖酵解和增强丝氨酸合成代谢。丝氨酸代谢与烟酰胺腺嘌呤二核苷磷酸（NADPH）、还原谷胱甘肽（GSH）合成相关。在前期研究基础上，本项目拟进一步研究肝癌干细胞通过丝氨酸的代谢重编程使其获得耐药性的可能性机制：丝氨酸合成代谢增强将产生更多的核苷酸合成底物和NADPH，而这些代谢产物有助于DNA损伤修复和消除活性氧（ROS）的毒害作用，促进肿瘤细胞存活，最终达到对化疗药物耐药的目的。本研究从一个新的视角探索肝癌干细胞化疗耐药的机制，以期通过干预丝氨酸代谢重编程增强化疗药物的敏感性。

Chemotherapy is one of the most common treatments for patients whom are diagnosed with cancer. However, the efficiency for hepatocellular carcinoma patients is less than 20%. Therefore, it is urgent to investigate the mechanism of chemotherapy resistance and explore effective treatment strategies for hepatocellular carcinoma. Our previous results showed that the rate-limiting enzymes of gluconeogenesis are downregulated in HCC tissues, which are well known as phosphoenolpyruvate carboxykinase(PEPCK),a key enzyme in gluconeogenesis. However, we recently found that cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), also known as PCK1, was upregulated in liver cancer stem like cells (TRCs). Surprisingly, up-regulated PCK1 in TRCs did not mediate gluconeogenesis but promoted glucose side-branch metabolism, including glycolysis and serine metabolic rearrangements. As we know, serine metabolism is associated with synthesis of NADPH and GSH. Based on those findings, we attempt to further investigate the chemotherapy is one of the most common treatments for patients whom are diagnosed with cancer. However, the efficiency for hepatocellular carcinoma patients is less than 20%. Therefore, it is urgent to investigate the mechanism of chemotherapy resistance and explore effective treatment strategies for hepatocellular carcinoma. Our previous results showed that the rate-limiting enzymes of gluconeogenesis are downregulated in HCC tissues, which are well known as phosphoenolpyruvate carboxykinase(PEPCK),a key enzyme in gluconeogenesis. However, we recently found that cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), also known as PCK1, was upregulated in liver cancer stem like cells (TRCs). Surprisingly, up-regulated PCK1 in TRCs did not mediate gluconeogenesis but promoted glucose side-branch metabolism, including glycolysis and serine metabolic rearrangements. As we know, serine metabolism is associated with synthesis of NADPH and GSH. Based on those findings, we attempt to further investigate the mechanism of serine metabolic rearrangements promoting chemotherapy resistance in TICs: during serine metabolism, some metabolites such as NADPH and GSH can increase the repair of DNA damage, reduce the toxicity of reactive oxygen species, promote the survival of tumor cells, and finally acquired the ability of chemotherapy resistance. This study highlights the novel mechanism of chemotherapy resistance in TRCs，which provide a new perspective view of chemotherapy for HCC through regulating serine metabolic rearrangement.