DPP4调控结肠癌细胞铁死亡的分子机制

Ferroptosis, a newly identified form of regulated cell death dependent on iron accumulation and lipid peroxidation, has become an active area of cancer research. Colorectal cancer is a common malignancy of the digestive system, deletion and mutation of tumor suppressor gene p53 is mainly responsible for its resistance to chemotherapy. Recently, the applicant firstly reported on Cell reports that colorectal cancer cells with p53 deletion and mutation were sensitive to ferroptosis, and proved that p53 affected DPP4 subcellular localization via direct protein interaction, thus to modulate DPP4 activity and ferroptosis. The previous study established a new theory of DPP4-dependent ferroptosis. Based on these findings, the applicant will use methods, including vector construction, RNA interference, gene transfection, chromatin immunoprecipitation, to further investigate the molecular mechanisms and structural basis of DPP4 involved in regulating ferroptosis in colorectal cancer cells, mainly focusing on the effects of DPP4 on the transcription function of p53 and the mechanism of DPP4 promoting lipid metabolism. This project is expected to reveal a new function of DPP4, and provide new strategies for precision medicine via targeting ferroptosis, which is of great significance in translational medicine.

铁死亡是一种依赖于铁聚集和脂质过氧化的细胞死亡新形式，正成为肿瘤研究的热点。结肠癌是常见的消化道恶性肿瘤，抑癌基因p53缺失和突变是目前化疗耐药的主要原因。申请人最近在Cell Reports上首次报道p53缺失和突变的结肠癌细胞对铁死亡诱导剂敏感，并且证明p53直接通过蛋白相互作用影响DPP4蛋白的亚细胞定位，从而影响DPP4活性和铁死亡发生。上述研究建立了DPP4依赖性铁死亡的新理论，申请人在此基础上拟采用载体构建、RNA干扰、基因转染、染色质免疫共沉淀等研究手段，在分子、细胞和动物水平，深入探讨DPP4调控结肠癌细胞铁死亡的分子机制和结构基础，重点探讨DPP4对p53转录功能的影响以及DPP4促进脂代谢的机制。开展本项目有望揭示DPP4的新功能，为靶向铁死亡的肿瘤精准治疗提供新的策略，具有重要的转化医学意义。

细胞的能量代谢异常是肿瘤的特征之一，也是产生凋亡抵抗的原因之一。铁死亡是一种依赖于铁聚集和脂质过氧化的非凋亡形式的细胞死亡，正成为肿瘤研究的热点。在前期的研究中，我们探讨了在葡萄糖代谢中发挥重要功能的DPP4是如何调节p53缺陷的结直肠癌细胞铁死亡。在此基础上，本项目进一步研究发现，葡萄糖剥夺可选择性地阻断system xc−抑制剂（erastin／SAS）诱导的铁死亡。基于siRNA文库的筛选发现，丙酮酸脱氢酶激酶4 (PDK4)通过阻断葡萄糖依赖的丙酮酸氧化进入三羧酸循环（TCA）以及随后的脂肪酸合成，是抗铁死亡的关键因素。开展本项目鉴定了铁死亡调控新蛋白，为靶向铁死亡的肿瘤精准治疗提供新的策略，具有重要的转化医学意义。