SIRT1去乙酰化IDH1调节结直肠癌糖代谢重编程及耐药性的机制研究

Drug resistance led to the failure of chemotherapy for colorectal cancer. Reprogramming of tumor glucose metabolism is closely related to chemotherapy resistance. Targeting tumor metabolism is expected to evaluate and improve the efficacy of chemotherapy for colorectal cancer. Our previous studies confirmed that the deacetylase SIRT1 was involved in the reprogramming of glucose metabolism in a variety of tumor cells, but its practical significance for tumor therapy has not been clear. Our preliminary results showed that SIRT1 was highly expressed in colorectal cancer tissues and participated in the deacetylation of isocitrate dehydrogenase 1 (IDH1), which is a key enzyme in glucose metabolism. Mass spectrometry of protein acetylation analysis in drug-resistant colorectal cancer tissues showed that deacetylation of IDH1 K115 was associated with drug resistance. Therefore, the idea is presented in this study that SIRT1 directly deacetylates IDH1 K115 and regulates reprogramming of glucose metabolism in colorectal cancer cells, thereby promoting chemotherapy resistance. Molecular biology assays, metabolic analysis, drug sensitivity assessment, and molecular imaging will be used to elucidate SIRT1-mediated IDH1 deacetylation in glucose metabolism regulation and drug resistance in colorectal cancer. The study aims to provide a new strategy for clinical intervention in colorectal cancer resistance by revealing specific molecular mechanisms.

耐药性的发生导致结直肠癌的化疗治疗失败。肿瘤糖代谢重编程与肿瘤耐药发生密切相关，靶向肿瘤代谢有望作为评估和改善结直肠癌化疗治疗效果的策略。申请人的前期研究证实去乙酰化酶SIRT1在多种肿瘤细胞中参与糖代谢重编程过程，但其对肿瘤治疗的现实意义此前尚不明确。预实验结果显示SIRT1在结直肠癌组织中高表达，并参与了糖代谢关键酶异柠檬酸脱氢酶1（IDH1）的去乙酰化调控。对耐药的结直肠癌组织进行蛋白质乙酰化修饰质谱分析，结果显示IDH1 K115位点的去乙酰化与结直肠癌的耐药性呈相关性。因此，本项目围绕“SIRT1直接去乙酰化IDH1 K115位点并调控结直肠癌细胞糖代谢重编程，进而促进细胞耐药性”这一设想，通过分子生物学技术、代谢分析、药物敏感性评价和分子影像手段对SIRT1介导的IDH1去乙酰化在结直肠癌糖代谢调控和耐药的功能进行阐述并揭示具体分子机制，旨在为临床干预结直肠癌耐药提供新的方法。

耐药性的发生导致结直肠癌的化疗治疗失败。肿瘤糖代谢重编程与肿瘤耐药发生密切相关，靶向肿瘤代谢有望作为评估和改善结直肠癌化疗治疗效果的策略。异柠檬酸脱氢酶1（IDH1）是三羧酸循环中的速率限制酶，调节细胞内氧化还原环境，帮助肿瘤细胞适应化疗药物暴露造成的恶劣条件。申请人在本项目的资助下，对SIRT1调控IDH1去乙酰化结直肠癌化疗耐药中的作用进行探究，发现在TNFα缺失下，IDH1 K115去乙酰化通过糖代谢中的氧化还原途径促进结直肠癌细胞的5-FU耐药性。因此，本项目围绕“SIRT1直接去乙酰化IDH1 K115位点并调控结直肠癌细胞糖代谢重编程，进而促进细胞耐药性”这一设想，通过分子生物学技术、代谢分析、药物敏感性评价和分子影像手段对SIRT1介导的IDH1去乙酰化在结直肠癌糖代谢调控和耐药的功能进行阐述并揭示具体分子机制，旨在为临床干预结直肠癌耐药提供新的方法。