Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea.
Center Research Institute, Samjin Pharm. Co., Ltd, Seoul 07794, Republic of Korea.
Cell Rep Med. 2023 Jan 17;4(1):100880. doi: 10.1016/j.xcrm.2022.100880. Epub 2023 Jan 4.
Glioblastoma (GBM) currently has a dismal prognosis. GBM cells that survive radiotherapy contribute to tumor progression and recurrence with metabolic advantages. Here, we show that diacylglycerol kinase B (DGKB), a regulator of the intracellular concentration of diacylglycerol (DAG), is significantly downregulated in radioresistant GBM cells. The downregulation of DGKB increases DAG accumulation and decreases fatty acid oxidation, contributing to radioresistance by reducing mitochondrial lipotoxicity. Diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the formation of triglycerides from DAG, is increased after ionizing radiation. Genetic inhibition of DGAT1 using short hairpin RNA (shRNA) or microRNA-3918 (miR-3918) mimic suppresses radioresistance. We discover that cladribine, a clinical drug, activates DGKB, inhibits DGAT1, and sensitizes GBM cells to radiotherapy in vitro and in vivo. Together, our study demonstrates that DGKB downregulation and DGAT1 upregulation confer radioresistance by reducing mitochondrial lipotoxicity and suggests DGKB and DGAT1 as therapeutic targets to overcome GBM radioresistance.
胶质母细胞瘤（GBM）目前的预后较差。放疗后存活的 GBM 细胞具有代谢优势，促进肿瘤进展和复发。在这里，我们表明，二酰基甘油激酶 B（DGKB）是二酰基甘油（DAG）细胞内浓度的调节剂，在耐辐射的 GBM 细胞中显著下调。DGKB 的下调会增加 DAG 的积累并减少脂肪酸氧化，通过减少线粒体脂毒性来促进放疗抵抗。二酰基甘油酰基转移酶 1（DGAT1）在电离辐射后增加，它催化 DAG 形成三酰基甘油。使用短发夹 RNA（shRNA）或 microRNA-3918（miR-3918）模拟物抑制 DGAT1 的基因抑制可抑制放疗抵抗。我们发现，克拉屈滨是一种临床药物，可激活 DGKB，抑制 DGAT1，并在体外和体内增强 GBM 细胞对放疗的敏感性。总之，我们的研究表明，DGKB 下调和 DGAT1 上调通过减少线粒体脂毒性赋予放疗抵抗性，并表明 DGKB 和 DGAT1 是克服 GBM 放疗抵抗性的治疗靶点。
