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Abstract
Glioblastoma Multiforme (GBM) is a malignant primary brain tumor. Radiotherapy, one of the standard treatments for GBM patients, could induce GBM radioresistance via rewiring cellular metabolism. However, the precise mechanism attributing to GBM radioresistance or targeting strategies to overcome GBM radioresistance are lacking. Here, we demonstrate that SLC25A22, a mitochondrial bi-directional glutamate transporter, is upregulated and showed uni-directionality from mitochondria to cytosol in radioresistant GBM cells, resulting in accumulating cytosolic glutamate. However, mitochondrial glutaminolysis-mediated TCA cycle metabolites and OCR are maintained constantly. The accumulated cytosolic glutamate enhances the glutathione (GSH) production and proline synthesis in radioresistant GBM cells. Increased GSH protects cells against ionizing radiation (IR)-induced reactive oxygen species (ROS) whereas increased proline, a rate-limiting substrate for collagen biosynthesis, induces extracellular matrix (ECM) remodeling, leading to GBM invasive phenotypes. Finally, we discover that genetic inhibition of SLC25A22 using miR-184 mimic decreases GBM radioresistance and aggressiveness both in vitro and in vivo. Collectively, our study suggests that SLC25A22 upregulation confers GBM radioresistance by rewiring glutamate metabolism, and SLC25A22 could be a significant therapeutic target to overcome GBM radioresistance.

Affiliations

Eunguk Shin 1, Byeongsoo Kim 1, Hyunkoo Kang 1, Haksoo Lee 1, Junhyung Park 1, JiHoon Kang 2, Eunho Park 3, Sunmi Jo 4, Hae Yu Kim 5, Jung Sub Lee 6, Jae-Myung Lee 7, HyeSook Youn 8, BuHyun Youn 9
1Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea.
2Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
3Ebiogen Inc., Seoul, Republic of Korea.
4Department of Radiation Oncology, Haeundae Paik Hospital, Inje University School of Medicine, Busan 48108, Republic of Korea.
5Department of Neurosurgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan 48108, Republic of Korea.
6Department of Orthopaedic Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan 49241, Republic of Korea.
7Department of Naval Architecture and Ocean Engineering, Pusan National University, Busan 46241, Republic of Korea.
8Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul 05006, Republic of Korea.
9Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea; Nuclear Science Research Institute, 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.