首都医科大学附属北京天坛医院张伟、江涛研究小组在研究中取得进展。他们发现了糖代谢重编程诱导的XRCC1乳酸化，赋予过表达ALDH1A3的胶质母细胞瘤的治疗抗性。该项研究成果发表在2024年8月6日出版的《细胞—代谢》上。

课题组发现ALDH1A3和PKM2之间的相互作用增强了后者的四聚体化，促进了胶质母细胞瘤干细胞(GSCs)中乳酸的积累。通过扫描积累乳酸的胶质母细胞瘤干细胞中乳酸化的蛋白质组，研究组发现XRCC1在赖氨酸247 (K247)位发生了乳酸化。乳酸化的XRCC1显示出对输入蛋白α更强的亲和力，允许XRCC1更大的核转运和增强的DNA修复。

通过小分子文库的高通量筛选，研究组发现D34-919能有效地破坏ALDH1A3-PKM2相互作用，阻止ALDH1A3介导的PKM2四聚化增强。体外和体内用D34-919治疗可增强放化疗诱导的胶质母细胞瘤细胞凋亡。总之，他们的研究结果表明，ALDH1A3介导的PKM2四聚化是改善高ALDH1A3表达的胶质母细胞瘤对放化疗反应的潜在治疗靶点。

据介绍，高ALDH1A3表达的胶质母细胞瘤(ALDH1A3^hi GBM)患者术后放化疗的获益有限。了解这些患者的耐药机制对于开发新的治疗方法至关重要。

附：英文原文

Title: Glycometabolic reprogramming-induced XRCC1 lactylation confers therapeutic resistance in ALDH1A3-overexpressing glioblastoma

Author: Guanzhang Li, Di Wang, You Zhai, Changqing Pan, Jiazheng Zhang, Chen Wang, Ruoyu Huang, Mingchen Yu, Yiming Li, Xing Liu, Yanwei Liu, Fan Wu, Zheng Zhao, Huimin Hu, Zhongfang Shi, Ulf Dietrich Kahlert, Tao Jiang, Wei Zhang

Issue&Volume: 2024/08/06

Abstract: Patients with high ALDH1A3-expressing glioblastoma (ALDH1A3hi GBM) show limited benefit from postoperative chemoradiotherapy. Understanding the mechanisms underlying such resistance in these patients is crucial for the development of new treatments. Here, we show that the interaction between ALDH1A3 and PKM2 enhances the latter’s tetramerization and promotes lactate accumulation in glioblastoma stem cells (GSCs). By scanning the lactylated proteome in lactate-accumulating GSCs, we show that XRCC1 undergoes lactylation at lysine 247 (K247). Lactylated XRCC1 shows a stronger affinity for importin α, allowing for greater nuclear transposition of XRCC1 and enhanced DNA repair. Through high-throughput screening of a small-molecule library, we show that D34-919 potently disrupts the ALDH1A3-PKM2 interaction, preventing the ALDH1A3-mediated enhancement of PKM2 tetramerization. In vitro and in vivo treatment with D34-919 enhanced chemoradiotherapy-induced apoptosis of GBM cells. Together, our findings show that ALDH1A3-mediated PKM2 tetramerization is a potential therapeutic target to improve the response to chemoradiotherapy in ALDH1A3hi GBM.

DOI: 10.1016/j.cmet.2024.07.011

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00282-1