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Abstract
Background: Glioblastoma Multiforme (GBM) is a malignant primary brain tumor in which the standard treatment, ionizing radiation (IR), achieves a median survival of about 15 months. GBM harbors glioblastoma stem-like cells (GSCs), which play a crucial role in therapeutic resistance and recurrence.

Methods: Patient-derived GSCs, GBM cell lines, intracranial GBM xenografts, and GBM sections were used to measure mRNA and protein expression and determine the related molecular mechanisms by qRT-PCR, immunoblot, immunoprecipitation, immunofluorescence, OCR, ECAR, live-cell imaging, and immunohistochemistry. Orthotopic GBM xenograft models were applied to investigate tumor inhibitory effects of glimepiride combined with radiotherapy.

Results: We report that GSCs that survive standard treatment radiation upregulate Speedy/RINGO cell cycle regulator family member A (Spy1) and downregulate CAP-Gly domain containing linker protein 3 (CLIP3, also known as CLIPR-59). We discovered that Spy1 activation and CLIP3 inhibition coordinately shift GBM cell glucose metabolism to favor glycolysis via two cellular processes: transcriptional regulation of CLIP3 and facilitating Glucose transporter 3 (GLUT3) trafficking to cellular membranes in GBM cells. Importantly, in combination with IR, glimepiride, an FDA-approved medication used to treat type 2 diabetes mellitus, disrupts GSCs maintenance and suppresses glycolytic activity by restoring CLIP3 function. In addition, combining radiotherapy and glimepiride significantly reduced GBM growth and improved survival in a GBM orthotopic xenograft mouse model.

Conclusions: Our data suggest that radioresistant GBM cells exhibit enhanced stemness and glycolytic activity mediated by the Spy1-CLIP3 axis. Thus, glimepiride could be an attractive strategy for overcoming radioresistance and recurrence by rescuing CLIP3 expression.

Affiliations

Hyunkoo Kang  1 , Sungmin Lee  1   2 , Kyeongmin Kim  1 , Jaewan Jeon  3 , Seok-Gu Kang  4   5 , HyeSook Youn  6 , Hae Yu Kim  7 , BuHyun Youn  8   9
1 Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea.
2 Present address: Institute of Bioinnovation Research, Kolon Life Science, Seoul, Republic of Korea.
3 Department of Radiation Oncology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
4 Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
5 Department of Medical Sciences, Yonsei University Graduate School, Seoul, Republic of Korea.
6 Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea.
7 Department of Neurosurgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
8 Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea. bhyoun72@pusan.ac.kr.
9 Department of Biological Sciences, Pusan National University, Busandaehak-ro 63beon-gil 2, Geumjeong-gu, Busan, 46241, Republic of Korea. bhyoun72@pusan.ac.kr.