Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Jilin Province Neuro-oncology Engineering Laboratory and Jilin Provincial Key Laboratory of Neuro-oncology, 126 Xiantai Road, Changchun, 130033, China.
Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Jilin Province Neuro-oncology Engineering Laboratory and Jilin Provincial Key Laboratory of Neuro-oncology, 126 Xiantai Road, Changchun, 130033, China.
Exp Cell Res. 2022 Nov 15;420(2):113358. doi: 10.1016/j.yexcr.2022.113358. Epub 2022 Sep 15.
Glioblastoma multiforme (GBM) is a common intracranial primary tumor of the central nervous system with high malignancy, poor prognosis, and short survival. Studies have shown that mitochondrial energy metabolism plays an important role in GBM chemotherapy resistance, suggesting that interrupting mitochondrial oxidative phosphorylation (OXPHOS) may improve GBM treatment. Human peptide deformylase (HsPDF) is a mitochondrial deformylase that removes the formylated methionine from the N-terminus of proteins encoded by mitochondrial DNA (mtDNA), thereby contributing to correct protein folding and participating in the assembly of the electron respiratory chain complex. In this study, we found that the expression of mtDNA-encoded proteins was significantly downregulated after treatment of GBM cells U87MG and LN229 with the HsPDF inhibitor, actinonin. In combination with temozolomide, a preferred chemotherapeutic medicine for GBM, the OXPHOS level decreased, mitochondrial protein homeostasis was unbalanced, mitochondrial fission increased, and the integrated stress response was activated to promote mitochondrial apoptosis. These findings suggest that HsPDF inhibition is an important strategy for overcoming chemoresistance of GBM cells.
多形性胶质母细胞瘤（GBM）是一种常见的颅内原发性中枢神经系统肿瘤，具有高度恶性、预后不良和生存期短的特点。研究表明，线粒体能量代谢在 GBM 化疗耐药中起重要作用，提示中断线粒体氧化磷酸化（OXPHOS）可能改善 GBM 的治疗效果。人肽脱甲酰基酶（HsPDF）是一种线粒体脱甲酰基酶，可从线粒体 DNA（mtDNA）编码的蛋白质的 N 端去除甲酰化甲硫氨酸，从而有助于正确的蛋白质折叠，并参与电子呼吸链复合物的组装。在本研究中，我们发现 HsPDF 抑制剂放线菌酮处理 GBM 细胞 U87MG 和 LN229 后，mtDNA 编码蛋白的表达显著下调。与替莫唑胺联合应用，后者是 GBM 的首选化疗药物，OXPHOS 水平降低，线粒体蛋白稳态失衡，线粒体裂变增加，整合应激反应被激活，从而促进线粒体凋亡。这些发现表明，抑制 HsPDF 是克服 GBM 细胞化疗耐药的重要策略。
