PO.MCB02.02 · 分子与细胞生物学
抑制线粒体蛋白MAGMAS可增加对标准治疗的敏感性
Inhibition of mitochondrial protein MAGMAS increases sensitivity to standard of care treatment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胶质母细胞瘤是一种高度侵袭性的中枢神经系统癌症,在美国每年每10万人中有3人罹患。大多数患者在初次诊断并接受标准治疗后的第一年内出现肿瘤复发。GBM的特征是高有丝分裂指数、侵袭脑内其他区域的能力以及调节肿瘤微环境(TME)的能力。对于复发性GBM患者,治疗选择极为有限,因为肿瘤对化疗的耐药性日益增强。化疗耐药可归因于多种因素,包括DNA损伤反应(DDR)、胶质瘤干细胞(GSC)、TME、衰老机制和代谢重编程。线粒体相关粒细胞巨噬细胞集落刺激因子分子(MAGMAS)是一种线粒体蛋白,也是内膜转位酶23(TIM23)复合物的亚基,通过将DNAJC19募集到TIM23复合物来调节蛋白向线粒体的转运。本研究旨在探讨MAGMAS在GBM肿瘤生物学及TMZ耐药机制中的作用。对公开数据库中MAGMAS/PAM16表达水平的计算分析显示,MAGMAS水平在复发性肿瘤中显著升高,并且在原发患者组织中与DNA修复酶O(6)-甲基鸟嘌呤-DNA甲基转移酶(MGMT)表达呈正相关。我们构建了表达shpam16构建体的基因修饰胶质瘤细胞,发现MAGMAS缺陷的胶质瘤细胞对包括TMZ、放疗和肿瘤电场治疗(TTF)在内的标准治疗更敏感。此外,我们发现沉默PAM16/MAGMAS降低了MGMT表达并减少了乳酸的胞外排泄。有趣的是,我们还发现细胞因子IL7和IL15在MAGMAS敲低细胞中显著上调。综上,我们的结果表明MAGMAS在化疗耐药、代谢重编程以及潜在的TME调节中发挥重要作用。通过靶向MAGMAS,我们未来可以营造有利条件,利用免疫治疗策略增强抗肿瘤反应。
查看英文原文 English abstract
Glioblastoma is a highly aggressive CNS cancer that affects 3 in 100,000 people every year in the U.S. The majority of patients experience tumor recurrence within the first year after initial diagnosis and after receiving standard of care treatment. GBM is characterized by its high mitotic index, capacity to invade other regions of the brain and modulate the tumor microenvironment (TME). Options are extremely limited for patients suffering from recurrent GBM as tumors become increasingly resistant to chemotherapy. Resistance to chemotherapy can be attributed to several factors that include DNA damage response (DDR), glioma stem cells (GSCs), TME, senescence mechanisms, and metabolic reprogramming. Mitochondria-associated granulocyte macrophage colony-stimulating factor molecule (MAGMAS), a mitochondria protein and subunit of the translocase of the inner membrane 23 (TIM23) complex, regulates protein trafficking into the mitochondria by recruiting DNAJC19 to the TIM23 complex. The present work was to investigate the role of MAGMAS in GBM tumor biology and mechanisms of resistance to TMZ. Computational analysis of MAGMAS/PAM16 expression levels from publicly available databases revealed that MAGMAS levels are significantly elevated in recurrent tumors and is positively correlated with the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) expression in primary patient tissues. We generated genetically modified glioma cells expressing shpam16 constructs and found that MAGMAS deficient glioma cells were sensitized to standard of care treatment that include TMZ, radiation and tumor treating fields (TTFs). Additionally, we discovered that silencing PAM16/MAGMAS reduced MGMT expression and reduced extracellular excretion of lactic acid. Interestingly, we also discovered that the cytokine IL7 and IL15 were significantly upregulated in MAGMAS KD cells. Taken together, our results demonstrate that MAGMAS plays an important role in chemotherapy resistance, metabolic reprogramming and potentially modulating the TME. By targeting MAGMAS, we can promote favorable conditions to enhance anti-tumor response using immunotherapy strategies in the future.
利益披露 Disclosure
J. J. Lepe, None..
C. Chen, None.