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Abstract
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.

Affiliations

Hyunkoo Kang 1, Haksoo Lee 1, Kyeongmin Kim 2, Eunguk Shin 1, Byeongsoo Kim 1, JiHoon Kang 3, Bohkyung Kim 4, Jung Sub Lee 5, Jae-Myung Lee 6, HyeSook Youn 7, BuHyun Youn 8
1Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea.
2Center Research Institute, Samjin Pharm. Co., Ltd, Seoul 07794, Republic of Korea.
3Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
4Department of Food Science and Nutrition, Pusan National University, Busan 46241, Republic of Korea.
5Department of Orthopaedic Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan 49241, Republic of Korea.
6Department of Naval Architecture and Ocean Engineering, Pusan National University, Busan 46241, Republic of Korea.
7Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul 05006, Republic of Korea.
8Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea; Department of Biological Sciences, Pusan National University, Busan 46241, Republic of Korea. Electronic address: bhyoun72@pusan.ac.kr.