Samuel Sabrina Francesca, Marsden Alistair James, Deepak Srihari, Rivero Francisco, Greenman John, Beltran-Alvarez Pedro
Biomedical Sciences, Faculty of Health Sciences, University of Hull, HU6 7RX Hull, UK.
Department of Neurosurgery, Hull Royal Infirmary, HU3 2JZ Hull, UK.
Proteomes. 2018 Oct 20;6(4):44. doi: 10.3390/proteomes6040044.
Glioblastomas (GBM) are the most common grade 4 brain tumours; patients have very poor prognosis with an average survival of 15 months after diagnosis. Novel research lines have begun to explore aberrant protein arginine methylation (ArgMe) as a possible therapeutic target in GBM and ArgMe inhibitors are currently in clinical trials. Enzymes known as protein arginine methyltransferases (PRMT1-9) can lead to mono- or di-ArgMe, and in the latter case symmetric or asymmetric dimethylation (SDMA and ADMA, respectively). Using the most common GBM cell line, we have profiled the expression of PRMTs, used ArgMe inhibitors as tools to investigate post-translational modifications cross-talk and measured the effect of ArgMe inhibitors on cell viability. We have identified novel SDMA events upon inhibition of ADMA in GBM cells and spheroids. We have observed cross-talk between ADMA and lysine acetylation in GBM cells and platelets. Treatment of GBM cells with furamidine, a PRMT1 inhibitor, reduces cell viability in 2D and 3D models. These data provide new molecular understanding of a disease with unmet clinical needs.
胶质母细胞瘤（GBM）是最常见的4级脑肿瘤；患者预后很差，诊断后平均生存期为15个月。新的研究方向已开始探索异常的蛋白质精氨酸甲基化（ArgMe）作为GBM可能的治疗靶点，目前ArgMe抑制剂正处于临床试验阶段。被称为蛋白质精氨酸甲基转移酶（PRMT1 - 9）的酶可导致单精氨酸甲基化或双精氨酸甲基化，在后一种情况下分别为对称或不对称二甲基化（分别为SDMA和ADMA）。使用最常见的GBM细胞系，我们分析了PRMTs的表达，使用ArgMe抑制剂作为工具来研究翻译后修饰的相互作用，并测量了ArgMe抑制剂对细胞活力的影响。我们在GBM细胞和球体中抑制ADMA后鉴定出了新的SDMA事件。我们在GBM细胞和血小板中观察到了ADMA与赖氨酸乙酰化之间的相互作用。用PRMT1抑制剂喷他脒处理GBM细胞可降低二维和三维模型中的细胞活力。这些数据为这种临床需求未得到满足的疾病提供了新的分子认识。
