Szeliga Monika, Albrecht Jan
Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
Neurochem Int. 2015 Sep;88:6-9. doi: 10.1016/j.neuint.2014.11.004. Epub 2014 Dec 18.
Glutamine (Gln) and glutamate (Glu) play pivotal roles in the malignant phenotype of brain tumors via multiple mechanisms. Glutaminase (GA, EC 3.5.1.2) metabolizes Gln to Glu and ammonia. Human GA isoforms are encoded by two genes: GLS gene codes for kidney-type isoforms, KGA and GAC, whereas GLS2 codes for liver-type isoforms, GAB and LGA. The expression pattern of both genes in different neoplastic cell lines and tissues implicated that the kidney-type isoforms are associated with cell proliferation, while the liver-type isoforms dominate in, and contribute to the phenotype of quiescent cells. GLS gene has been demonstrated to be regulated by oncogene c-Myc, whereas GLS2 gene was identified as a target gene of p53 tumor suppressor. In glioblastomas (GBM, WHO grade IV), the most aggressive brain tumors, high levels of GLS and only traces or lack of GLS2 transcripts were found. Ectopic overexpression of GLS2 in human glioblastoma T98G cells decreased their proliferation and migration and sensitized them to the alkylating agents often used in the chemotherapy of gliomas. GLS silencing reduced proliferation of glioblastoma T98G cells and strengthen the antiproliferative effect evoked by previous GLS2 overexpression.
谷氨酰胺（Gln）和谷氨酸（Glu）通过多种机制在脑肿瘤的恶性表型中发挥关键作用。谷氨酰胺酶（GA，EC 3.5.1.2）将Gln代谢为Glu和氨。人类GA同工型由两个基因编码：GLS基因编码肾型同工型KGA和GAC，而GLS2编码肝型同工型GAB和LGA。这两个基因在不同肿瘤细胞系和组织中的表达模式表明，肾型同工型与细胞增殖相关，而肝型同工型在静止细胞的表型中占主导并对其有贡献。已证明GLS基因受癌基因c-Myc调控，而GLS2基因被确定为p53肿瘤抑制因子的靶基因。在最具侵袭性的脑肿瘤胶质母细胞瘤（GBM，世界卫生组织IV级）中，发现GLS水平高，而GLS2转录本仅有微量或缺乏。在人胶质母细胞瘤T98G细胞中异位过表达GLS2可降低其增殖和迁移，并使其对胶质瘤化疗中常用的烷化剂敏感。沉默GLS可降低胶质母细胞瘤T98G细胞的增殖，并增强先前GLS2过表达所引发的抗增殖作用。
