방사선의학 웹진

바로가기  >

이달의 연구자 바로가기 Click!

Abstract
Glioblastoma (GBM) is an aggressive brain tumor with a poor prognosis due to its resistance to radiotherapy. Epidermal growth factor receptor variant III (EGFRvIII), a common mutation in GBM, promotes radioresistance through ligand-independent activation. We hypothesized that membrane flexibility influences EGFRvIII activation and enhances resistance. Bone marrow stromal antigen 2 (BST2, CD317, or TETHERIN) was identified as a key mediator linking membrane dynamics to EGFRvIII-driven survival signaling. Radiation-induced changes in membrane flexibility amplified BST2 activity, stabilizing lipid rafts and promoting EGFRvIII clustering. Pharmacological inhibition of BST2 with arbutin, an FDA-approved compound, disrupted this mechanism, increasing GBM radiosensitivity by enhancing mitochondrial reactive oxygen species (ROS) production and apoptosis. Additionally, BST2 downregulation impaired de novo lipogenesis and reduced lipid droplet accumulation, highlighting its role in metabolic reprogramming. In orthotopic xenograft models, BST2 inhibition suppressed tumor growth and prolonged survival. These findings establish BST2 as a key regulator of membrane-driven radioresistance in GBM. Targeting BST2-mediated membrane remodeling may provide a novel therapeutic strategy to enhance radiotherapy efficacy.

방사선 조사에 의해 BST2 발현이 증가하면 세포막의 order 상태가 증가하고, 그 결과 EGFRvIII 활성이 촉진되어 암세포의 생존과 악성화를 돕게 됩니다. 이 과정에서 SREBP 전사인자가 활성화되어 ACLY, FASN, ACC, SCD와 같은 지방 합성 관련 유전자 발현을 증가시키며, de novo lipogenesis 및 lipid droplet 축적이 일어납니다. 이는 미토콘드리아 β-oxidation을 억제하여 ROS 생성을 줄이고, 교모세포종의 방사선 저항성을 강화하는 기전으로 작용합니다. 반대로, FDA 승인 물질인 Arbutin을 통해 BST2를 억제하면 세포막의 order 상태가 감소하고 EGFRvIII 활성이 저해되어, lipogenesis 감소–ROS 증가–세포사멸 촉진으로 이어져 방사선 치료 효과가 향상될 수 있습니다.

Affiliations

Haksoo Lee 1 2, Dahye Kim 1, Byeongsoo Kim 1, Eunguk Shin 1 3, Hyunkoo Kang 4, Jae-Myung Lee 5 6, HyeSook Youn 7, BuHyun Youn 8 9 10
1Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea.
2Institute for Future Earth, Pusan National University, Busan, 46241, Republic of Korea.
3Joonghun Pharmaceutical Co.Ltd, Seoul, 07236, Republic of Korea.
4Department of Neurosurgery, Yale School of Medicine, New Haven, CT, 06510, USA.
5Department of Naval Architecture and Ocean Engineering, Pusan National University, Busan, 46241, Republic of Korea.
6Hydrogen Ship Technology Center, 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. bhyoun72@pusan.ac.kr.
9Nuclear Science Research Institute, Pusan National University, Busan, 46241, Republic of Korea. bhyoun72@pusan.ac.kr.
10Department of Biological Sciences, Pusan National University, Busan, 46241, Republic of Korea. bhyoun72@pusan.ac.kr.