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Abstract
Overcoming therapeutic resistance in glioblastoma (GBM) is an essential strategy for improving cancer therapy. However, cancer cells possess various evasion mechanisms, such as metabolic reprogramming, which promote cell survival and limit therapy. The diverse metabolic fuel sources that are produced by autophagy provide tumors with metabolic plasticity and are known to induce drug or radioresistance in GBM. This study determined that autophagy, a common representative cell homeostasis mechanism, was upregulated upon treatment of GBM cells with ionizing radiation (IR). Nuclear receptor binding factor 2 (NRBF2)-a positive regulator of the autophagy initiation step-was found to be upregulated in a GBM orthotopic xenograft mouse model. Furthermore, ATP production and the oxygen consumption rate (OCR) increased upon activation of NRBF2-mediated autophagy. It was also discovered that changes in metabolic state were induced by alterations in metabolite levels caused by autophagy, thereby causing radioresistance. In addition, we found that lidoflazine-a vasodilator agent discovered through drug repositioning-significantly suppressed IR-induced migration, invasion, and proliferation by inhibiting NRBF2, resulting in a reduction in autophagic flux in both in vitro models and in vivo orthotopic xenograft mouse models. In summary, we propose that the upregulation of NRBF2 levels reprograms the metabolic state of GBM cells by activating autophagy, thus establishing NRBF2 as a potential therapeutic target for regulating radioresistance of GBM during radiotherapy.

Affiliations

Jeongha Kim 1, Hyunkoo Kang 1, Beomseok Son 2, Min-Jung Kim 3 4, JiHoon Kang 5, Kang Hyun Park 6 7, Jaewan Jeon 8, Sunmi Jo 8, Hae Yu Kim 9, HyeSook Youn 10, BuHyun Youn 11 12
1Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea.
2siRNAgen Therapeutics, Daejeon, 34302, Republic of Korea.
3Nuclear Science Research Institute, Pusan National University, Busan, 46241, Republic of Korea.
4Department of Naval Architecture and Ocean Engineering, Pusan National University, Busan, 46241, Republic of Korea.
5Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
6Department of Chemistry, Pusan National University, Busan, 46241, Republic of Korea.
7SoulDot Co., Ltd, Pusan National University, Busan, 46241, Republic of Korea.
8Department of Radiation Oncology, Haeundae Paik Hospital, Inje University School of Medicine, Busan, 48108, Republic of Korea.
9Department of Neurosurgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, 48108, Republic of Korea.
10Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea. hsyoun@sejong.ac.kr.
11Department of Integrated Biological Science, Pusan National University, Busan, 46241, Republic of Korea. bhyoun72@pusan.ac.kr.
12Department of Biological Sciences, Pusan National University, Busan, Republic of Korea. bhyoun72@pusan.ac.kr.