丙酮酸激酶M2亚型在肿瘤放疗耐受过程中的作用及机制研究

Increasing evidence suggests that many types of cancers contain a population of cells that display stem cell properties. These cells are called cancer stem cells (CSCs). They are virtually resistant to radiation, and may contribute to treatment resistance and recurrence. Therefore, therapies specifically targeting CSCs will likely be needed for complete tumor eradication. In this project, we will use Glioma stem cells (GSCs), which were separated from glioma patient, as research model. We will demonstrate the role of PKM2 in the regulation of DNA repair system, which is enhanced in CSCs. This project may provide insights into the identification of potential therapeutic targets and development of novel innovative therapies to CSCs..

随着肿瘤干细胞（Cancer stem cells, CSCs）概念的提出，CSCs被认为是放疗耐受和癌症复发的原因之一。对CSCs放疗耐受机制的研究有利于提高CSCs对放疗的敏感性，从而最终治愈肿瘤。本项目将神经胶质瘤病人标本中分离的胶质瘤干细胞系（Glioma stem cells， GSCs）作为研究模型，以肿瘤细胞代谢的关键酶PKM2作为为研究切入点，重点研究肿瘤细胞增强的DNA损伤修复系统的调控机制，从而为肿瘤干细胞的治疗找到有效的用药靶点。

化疗是目前临床上治疗恶性肿瘤的最重要手段之一，然而肿瘤细胞常常会对化疗药物产生耐药，导致化疗失败，肿瘤复发。DNA作为射线和细胞毒性治疗对细胞作用的关键靶点，其损伤后迅速修复是放化疗耐受的关键原因。丙酮酸激酶M2（PKM2）是糖酵解通路中的关键酶，其在肿瘤细胞增殖中起重要作用。最近，有研究表明PKM2参与细胞凋亡调控，然而机制并不清楚。本项目以PKM2作为研究切入点着重阐述了：1）PKM2参与肿瘤细胞对抗Etopside、Paclitaxel、炎症因子及氧化应激导致的细胞凋亡的分子机制；2）PKM2促进肿瘤细胞存活的内在分子机制。研究结果发现1）PKM2通过稳定BCL2蛋白水平，从而促进肿瘤细胞对化疗药物、炎症因子及氧化应激损伤耐受；2）PKM2通过FACT复合物调控染色质中γH2AX水平，进而促进肿瘤细胞DNA损伤修复。