PRMT5 作为胶质母细胞瘤治疗的一个有潜力的药物靶点。
PRMT5 as a druggable target for glioblastoma therapy.
机构信息
The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas.
Department of Neurological Surgery, College of Medicine, The Ohio State University, Columbus, Ohio.
出版信息
Neuro Oncol. 2018 May 18;20(6):753-763. doi: 10.1093/neuonc/nox206.
BACKGROUND
In spite of standard multimodal therapy consisting of surgical resection followed by radiation and concurrent chemotherapy, prognosis for glioblastoma (GBM) patients remains poor. The identification of both differentiated and undifferentiated "stem cell like" populations in the tumor highlights the significance of finding novel targets that affect the heterogeneous tumor cell population. Protein arginine methyltransferase 5 (PRMT5) is one such candidate gene whose nuclear expression correlates with poor survival and has been reported to be required for survival of differentiated GBM cells and self-renewal of undifferentiated GBM cells. In the current study we screened the specificity and efficacy of 4 novel PRMT5 inhibitors in the treatment of GBM.
METHODS
Efficacies of these inhibitors were screened using an in vitro GBM neurosphere model and an in vivo intracranial zebrafish model of glioma. Standard molecular biology methods were employed to investigate changes in cell cycle, growth, and senescence.
RESULTS
In vitro and in vivo studies revealed that among the 4 PRMT5 inhibitors, treatment of GBM cells with compound 5 (CMP5) mirrored the effects of PRMT5 knockdown wherein it led to apoptosis of differentiated GBM cells and drove undifferentiated primary patient derived GBM cells into a nonreplicative senescent state.
CONCLUSION
In vivo antitumor efficacy combined with the specificity of CMP5 underscores the importance of developing it for translation.
背景
尽管标准的多模式治疗包括手术切除后放疗和同步化疗，但胶质母细胞瘤（GBM）患者的预后仍然很差。肿瘤中分化和未分化的“干细胞样”群体的鉴定突出了寻找影响异质性肿瘤细胞群体的新靶标的重要性。蛋白精氨酸甲基转移酶 5（PRMT5）是这样的候选基因之一，其核表达与不良预后相关，并被报道是分化的 GBM 细胞存活和未分化的 GBM 细胞自我更新所必需的。在本研究中，我们筛选了 4 种新型 PRMT5 抑制剂治疗 GBM 的特异性和疗效。
方法
使用体外 GBM 神经球模型和体内颅内斑马鱼胶质瘤模型筛选这些抑制剂的疗效。采用标准的分子生物学方法研究细胞周期、生长和衰老的变化。
结果
体外和体内研究表明，在 4 种 PRMT5 抑制剂中，用化合物 5（CMP5）处理 GBM 细胞，其作用类似于 PRMT5 敲低，导致分化的 GBM 细胞凋亡，并促使未分化的原代患者来源的 GBM 细胞进入非复制性衰老状态。
结论
体内抗肿瘤疗效结合 CMP5 的特异性强调了开发它用于转化的重要性。
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