Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany.
Cell Death Dis. 2022 Jul 22;13(7):641. doi: 10.1038/s41419-022-05098-9.
Oncogenic mutations in metabolic genes and associated oncometabolite accumulation support cancer progression but can also restrict cellular functions needed to cope with DNA damage. For example, gain-of-function mutations in isocitrate dehydrogenase (IDH) and the resulting accumulation of the oncometabolite D-2-hydroxyglutarate (D-2-HG) enhanced the sensitivity of cancer cells to inhibition of poly(ADP-ribose)-polymerase (PARP)1 and radiotherapy (RT). In our hand, inhibition of the mitochondrial citrate transport protein (SLC25A1) enhanced radiosensitivity of cancer cells and this was associated with increased levels of D-2-HG and a delayed repair of radiation-induced DNA damage. Here we aimed to explore the suggested contribution of D-2-HG-accumulation to disturbance of DNA repair, presumably homologous recombination (HR) repair, and enhanced radiosensitivity of cancer cells with impaired SLC25A1 function. Genetic and pharmacologic inhibition of SLC25A1 (SLC25A1i) increased D-2-HG-levels and sensitized lung cancer and glioblastoma cells to the cytotoxic action of ionizing radiation (IR). SLC25A1i-mediated radiosensitization was abrogated in MEFs with a HR-defect. D-2-HG-accumulation was associated with increased DNA damage and delayed resolution of IR-induced γH2AX and Rad51 foci. Combining SLC25A1i with PARP- or the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs)-inhibitors further potentiated IR-induced DNA damage, delayed DNA repair kinetics resulting in radiosensitization of cancer cells. Importantly, proof of concept experiments revealed that combining SLC25A1i with IR without and with PARPi also reduced tumor growth in the chorioallantoic membrane (CAM) model in vivo. Thereby SLC25A1i offers an innovative strategy for metabolic induction of context-dependent lethality approaches in combination with RT and clinically relevant inhibitors of complementary DNA repair pathways.
代谢基因的致癌突变和相关的致癌代谢产物积累支持癌症的进展，但也会限制细胞应对 DNA 损伤所需的功能。例如，异柠檬酸脱氢酶 (IDH) 的功能获得性突变和由此产生的致癌代谢产物 D-2-羟戊二酸 (D-2-HG) 的积累增强了癌细胞对聚 (ADP-核糖) -聚合酶 (PARP)1 和放射治疗 (RT) 的敏感性。在我们的研究中，抑制线粒体柠檬酸转运蛋白 (SLC25A1) 增强了癌细胞的放射敏感性，这与 D-2-HG 水平的增加以及辐射诱导的 DNA 损伤修复的延迟有关。在这里，我们旨在探索 D-2-HG 积累对 DNA 修复的干扰的贡献，推测是同源重组 (HR) 修复，以及 SLC25A1 功能受损的癌细胞的放射增敏作用。SLC25A1 的遗传和药物抑制 (SLC25A1i) 增加了 D-2-HG 水平，并使肺癌和神经胶质瘤细胞对电离辐射 (IR) 的细胞毒性作用敏感。在 HR 缺陷的 MEFs 中，SLC25A1i 介导的放射增敏作用被阻断。D-2-HG 积累与增加的 DNA 损伤和 IR 诱导的 γH2AX 和 Rad51 焦点的延迟解决有关。将 SLC25A1i 与 PARP 或 DNA 依赖性蛋白激酶 (DNA-PKcs) 的催化亚单位抑制剂联合使用进一步增强了 IR 诱导的 DNA 损伤，延迟了 DNA 修复动力学，从而使癌细胞放射增敏。重要的是，概念验证实验表明，在体内的绒毛尿囊膜 (CAM) 模型中，将 SLC25A1i 与无 PARPi 和有 PARPi 的 IR 联合使用也能减少肿瘤生长。因此，SLC25A1i 为代谢诱导与 RT 和互补 DNA 修复途径的临床相关抑制剂相结合的上下文相关致死性方法提供了一种创新的策略。
