结直肠癌细胞代谢中SIRT2调控PEPCK1乙酰化的分子机制

Metabolic changes is an important biological characteristic of tumor cells: cancer cells uptake a large amount of glucose; simultaneously, a large amount of glutamine also uptaked by cancer cells for the process of tumor proliferation. Metabolism intervention is a new strategy of anti-cancer therapy, but no desired effect was received when inhibit glucose or glutamine utilization alone, because there is a strong adaptability in tumor metabolism: glucose and glutamine can be converted to each other. Therefore, the target protein which co-regulation of glucose and glutamine is the key point in reversing tumor metabolism and cancer treatment. Our previous work suggests phosphoenolpyruvate carboxylase kinase 1 (PEPCK1) is the rate-limiting enzyme in gluconeogenesis which involved in production of glucose and utilization of glucose and glutamine. Meanwhile, function and protein level of PEPCK1 is regulated by NAD-dependent deacetylase sirtuin-2 (SIRT2) in colorectal cancer. As a result, we hypothesized: SIRT2 / PEPCK1 acetylation is the key pathway in synergistic use of glucose and glutamine, meanwhile tumor growth can be suppressed by PEPCK1 degradation. The current project aims to explore the function of SIRT2 / PEPCK1 acetylation signal pathway in colorectal cancer metabolism and the rapeutic targets in colorectal cancer treatment.

能量代谢改变是肿瘤的重要生物学特征：肿瘤会同时摄取大量葡萄糖及谷氨酰胺。干预能量代谢是抗肿瘤治疗的新领域，由于葡萄糖和谷氨酰胺可以相互补充，单独抑制葡萄糖或者谷氨酰胺均未收到理想效果。因此，寻找协同调控葡萄糖和谷氨酰胺代谢的关键靶点蛋白、通过阻断此关键蛋白实现对两种能源物质利用的共同阻断，是抑制肿瘤的关键。我们前期工作提示：在结直肠癌中，磷酸烯醇式丙酮酸羧激酶1(PEPCK1)促进了肿瘤细胞对葡萄糖和谷氨酰胺的利用；NAD依赖的去乙酰化酶2(SIRT2)通过乙酰化修饰调节了PEPCK1的蛋白水平和功能。因此我们提出假说：SIRT2/PEPCK1乙酰化调节信号通路是协同调控结直肠癌葡萄糖和谷氨酰胺利用的关键靶点蛋白，通过降解该蛋白，可以达到干预能量代谢、抑制肿瘤增殖的目的。本研究旨在探讨SIRT2/PEPCK1乙酰化调节信号通路对结直肠癌能量代谢的作用，为抗肿瘤治疗提供理论依据。

能量代谢改变是肿瘤的重要生物学特征：肿瘤会同时摄取大量葡萄糖及谷氨酰胺。干预能量代谢是抗肿瘤治疗的新领域，由于葡萄糖和谷氨酰胺可以相互补充，单独抑制葡萄糖或者谷氨酰胺均未收到理想效果。因此，寻找协同调控葡萄糖和谷氨酰胺代谢的关键靶点蛋白、通过阻断此关键蛋白实现对两种能源物质利用的共同阻断，是抑制肿瘤的关键。我们的工作提示：在结直肠癌中，磷酸烯醇式丙酮酸羧激酶1(PEPCK1)促进了肿瘤细胞对葡萄糖和谷氨酰胺的利用；NAD依赖的去乙酰化酶2(SIRT2)通过乙酰化修饰调节了PEPCK1的蛋白水平和功能。我们进一步发现，SIRT2/PEPCK1乙酰化调节信号通路是协同调控结直肠癌葡萄糖和谷氨酰胺利用的关键靶点蛋白，通过降解该蛋白，可以达到干预能量代谢、抑制肿瘤增殖的目的。本研究旨在探讨SIRT2/PEPCK1乙酰化调节信号通路对结直肠癌能量代谢的作用，为抗肿瘤治疗提供理论依据。