NRBF2-mediated autophagy contributes to metabolite replenishment and radioresistance in glioblastoma

• Authors: Jeongha Kim, Pusan National University; Hyunkoo Kang, Pusan National University; Beomseok Son, siRNAgen Therapeutics; Min-Jung Kim, Pusan National University; JiHoon Kang, Emory University; Kang Hyun Park, Pusan National University; Jaewon Jeon, Inje University; Sunmi Jo, Inje University; Hae Yu Kim, Inje University; HyeSook Youn, Sejong University; BuHyun Youn, Pusan National University
• Journal Title: EXPERIMENTAL AND MOLECULAR MEDICINE
• Volume: Volume 54, Number 11
• Publisher: SPRINGERNATURE | 2022-11-04, Pages 1872-1885
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s12276-022-00873-2
• Subjects: Health Sciences, Medicine and Surgery; Health Sciences, Oncology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; Medicine, Research & Experimental; Research & Experimental Medicine; 2-ENOYL THIOESTER REDUCTASE; BREAST-CANCER CELLS; LUNG-CANCER; TUMOR; RESISTANCE; MIGRATION; PHOSPHORYLATION; INHIBITION; P53

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.