방사선의학 웹진

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Abstract
Background: Glioblastoma (GBM) is an aggressive brain tumor characterized by a poor prognosis and resistance to radiotherapy. Although multiple mechanisms of radioresistance have been proposed, the contribution of membrane-driven metabolic adaptations to radioresistance remains poorly understood.

Methods: The role of UDP-glucose ceramide glucosyltransferase (UGCG) was investigated using radioresistant GBM cell lines and in vivo xenograft models. After inhibiting UGCG function through genetic or pharmacological (miglustat) approaches, we assessed the effects on lipid raft integrity, localization of the ASCT2 transporter, glutamine uptake, oxidative stress, and radiosensitivity.

Results: UGCG was upregulated in radioresistant GBM cells and promoted lipid raft stabilization. This facilitated the membrane recruitment of the glutamine transporter ASCT2 (SLC1A5), thereby sustaining redox homeostasis under radiation stress. Genetic or pharmacological inhibition of UGCG disrupted lipid raft integrity, impaired ASCT2 localization, reduced glutamine uptake, and increased oxidative stress, leading to enhanced radiosensitivity. In GBM xenograft models, UGCG inhibition combined with radiotherapy significantly suppressed tumor growth and extended survival.

Conclusions: These findings reveal a previously underexplored, membrane-centric mechanism of radioresistance in which UGCG orchestrates lipid raft remodeling to facilitate glutamine-dependent redox balance. This highlights UGCG as a potential therapeutic target to enhance the efficacy of radiotherapy in GBM.

Affiliations

Haksoo Lee # 1 2, Dahye Kim # 1, Byeongsoo Kim 1, DongJoo Joung 2 3, Jaewan Jeon 4, Tae-Oh Kim 5, HyeSook Youn 6, BuHyun Youn 7 8 9
1Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea.
2Institute for Future Earth, Pusan National University, Busan, Republic of Korea.
3Department of Oceanography, Pusan National University, Busan, Republic of Korea.
4Department of Radiation Oncology, Haeundae Paik Hospital, Inje University School of Medicine, Busan, Republic of Korea.
5Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Republic of Korea.
6Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea.
7Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea. bhyoun72@pusan.ac.kr.
8Nuclear Science Research Institute, Pusan National University, Busan, Republic of Korea. bhyoun72@pusan.ac.kr.
9Department of Biological Sciences, Pusan National University, Busan, Republic of Korea. bhyoun72@pusan.ac.kr.
#Contributed equally.