AMPK介导Sp1磷酸化修饰调控胆囊癌低糖应激敏感性的作用机制

糖酵解靶向治疗是肿瘤治疗的重要研究方向，但胆囊癌细胞对低糖应激具有极强抵抗能力进而导致相关药物的耐药。申请人前期研究发现，低糖应激下胆囊癌细胞AMPK激活，介导Sp1磷酸化修饰，抑制SOD2转录并激活PI3K/AKT通路启动自我保护机制。本项目根据前期初步结果，将深入阐明胆囊癌细胞对低糖应激耐受的全新分子机制，即低糖应激下AMPK激活并与Sp1相互作用，诱导其Ser2位点磷酸化，促进Sp1泛素化降解并抑制Sp1入核；由此，Sp1所介导的下游SOD2转录受到抑制，积聚的ROS促进PIK3CD转录和AKT激活。与此同时，AKT激活可进一步提高Sp1磷酸化水平，产生对抗能量应激的正反馈效应。本研究将为胆囊癌代谢类靶向药物耐药提供理论依据和新的临床治疗方案。

Glycolysis-targeting therapy is an important choice in cancer treatment. However, gallbladder cancer showed strong resistance to glucose deprivation stress. Our previous studies found that AMPK was activated in gallbladder cancer cells under glucose deprivation stress and promoted phosphorylation modification of Sp1, which leads to down-regulation of SOD2 transcription, promotes PI3K/AKT signaling and initiates self-protection program of cancer cells. According to previous results, we are trying to illustrate new molecular mechanism of resistance of GBC to glucose deprivation stress. Under glucose deprivation stress, AMPK interacted with Sp1 and promoted Sp1 Ser2 phosphorylation, inducing Sp1 degradation by ubiquitination. Sp1 down-regulation inhibits SOD2 expression. Then accumulated ROS enhanced PIK3CD transcription and activated AKT, which initiated anti-apoptotic mechanism in energy stress. At the same time, AKT activation further improved Sp1 phosphorylation and achieved a positive feedback effect against energy stress. This study will provide a theoretical basis and a new therapeutic scheme for metabolic targeting drug resistance in gallbladder cancer.