肝激酶B1（LKB1）通过磷酸化乙酰辅酶A羧化酶（ACC）抑制头颈部鳞状细胞癌生长的机制研究

Cancer cell metabolic reprogramming is one of the most significant features of tumor growth, in which Acetyl-CoA carboxylase (ACC) as a key enzyme of fatty acid metabolism plays an important role. Live kinase B1 (LKB1) regulates its downstream proteins, reducing intracellular energy consumption to balance metabolic homeostasis to inhibit tumor growth. We previously found that LKB1 and Acetyl-CoA carboxylase (ACC) have interactions, the levels of fatty acid synthesis and oxidation were significantly increased when inhibition of LKB1. And also ACC activated abnormally associated with tumor growth and drug resistance in head and neck squamous cell carcinoma (HNSCC). Accordingly, the above results suggest that “LKB1 regulates ACC phosphorylation affects the growth of HNSCC”. (1) This study was to investigate the relationship between the expression of LKB1, ACC isoenzyme, and phosphorylation in HNSCC; (2) To elucidate the mechanism of LKB1directly regulates ACC, and the effect on intracellular energy levels, fatty acid metabolic pathways, and tumor growth in vitro and in vivo. It is expected to demonstrate the hypothesis that LKB1 is an important metabolite with definite regulatory effects during tumor growth, explore the potential for the treatment of cancer and targeted therapy.

肿瘤细胞代谢重编程是肿瘤生长的最显著特征之一，乙酰辅酶A羧化酶（ACC）作为脂肪酸代谢的关键酶在其中起着重要作用。肝激酶B1（LKB1）可调控其下游蛋白，减少胞内能量消耗以平衡代谢稳态来抑制肿瘤生长。我们前期发现LKB1与ACC相互作用，抑制LKB1后脂肪酸合成与氧化水平均显著升高；并且ACC在进展期头颈部鳞癌中异常活化，促进肿瘤生长及耐药。上述结果提示：“LKB1有可能通过磷酸化ACC下调脂肪酸代谢水平来抑制头颈部鳞癌的生长”。本项目从ACC磷酸化入手，拟研究：（1）头颈部鳞癌中LKB1、ACC同工酶及磷酸化的表达与肿瘤生长预后的关系；（2）体内外实验证实LKB1调控ACC的机制，及其对细胞内能量水平、脂肪酸代谢通路和肿瘤生长等恶性表型的影响。预期有望证实上述科学问题，探讨在肿瘤生长过程中LKB1是具有明确调控作用的重要代谢物，研究并探索其作为治疗肿瘤生长药物靶点的潜在可能性。

肿瘤细胞的代谢异常是其区别于正常细胞的主要特征之一，在肿瘤的进展中发挥着重要作用，研究肿瘤细胞的代谢改变，并以此寻找新的治疗手段日益受到重视，成为世界肿瘤学界的研究热点。乙酰辅酶A羧化酶（ACC）作为脂肪酸 代谢的关键酶在其中起着重要作用。肝激酶B1（LKB1）可调控其下游蛋白，减少胞内能量消耗 以平衡代谢稳态来抑制肿瘤生长。代谢旺盛的肿瘤细胞主要依赖于胞外谷氨酰胺的摄入，氨基酸转运蛋白ASCT2是负责从胞外摄入谷氨酰胺的重要转运蛋白。我们主要研究：LKB1与脂肪酸合成氧化水平密切相关；体内外实验证实LKB1调控ACC的机制，及其对细胞内能量水平、脂肪酸代谢通路和肿瘤生长等恶性表型的影响；筛选出在三种头颈部鳞癌细胞系中均能与ASCT2共同沉淀的蛋白RACK1和ANXA2，并且初步研究发现降低RACK1和ANX A2表达后，头颈部鳞癌细胞谷氨酰胺摄入受到抑制，可以考虑以脂肪酸代谢和ASCT2代谢为靶点，作为糖代谢途径的有利补充，以全新的思路取得开拓性的成果，为代谢通路的抑制提供新的视野和思路，拓展肿瘤代谢领域的科学前沿。