Androgen receptor: a potential therapeutic target for glioblastoma.
Androgen receptor: a potential therapeutic target for glioblastoma.
复制标题
DOI：
10.18632/oncotarget.25007
复制
发表时间：
2018-04-13
期刊：
影响因子：
--
通讯作者：
Lavon I
中科院分区：
文献类型：
--
作者：
Zalcman N;Canello T;Ovadia H;Charbit H;Zelikovitch B;Mordechai A;Fellig Y;Rabani S;Shahar T;Lossos A;Lavon I
胶质母细胞瘤患者的中位生存时间仍然很差（14.6个月），部分原因是缺乏有效的治疗。我们观察到雄激素受体（AR）在胶质母细胞瘤中在DNA、RNA和蛋白质水平扩增。AR基因在27%的男性（n=22）和38.2%的女性（n=21）胶质母细胞瘤标本中扩增。AR-RNA在93%（n=30）中过表达（>2.5倍），并且AR蛋白在56%的胶质母细胞瘤样品（n=16）中被诱导（> 2倍）。30%的胶质母细胞瘤（n=21）还表达缺乏配体结合结构域的组成型活性AR剪接变体（AR-V7/AR 3）。根据这些发现，我们研究了雄激素受体在体外和体内的药理学抑制作用，以及在胶质母细胞瘤细胞系中受体的遗传沉默。AR拮抗剂，诱导浓度依赖性死亡的胶质母细胞瘤细胞系，以及在两个胶质瘤启动细胞系。通过siRNA沉默AR表达诱导三种测试的胶质母细胞瘤细胞系中的细胞死亡。Enzalutamide经口给予皮下移植人胶质瘤的裸鼠后，肿瘤体积缩小72%（p=0.0027）。AR-V7/AR 3在胶质母细胞瘤中的存在，连同显示细胞系中全长AR的遗传沉默和AR的药理学抑制在体内和体外诱导GBM细胞死亡的本数据，指出了AR在GBM存活中的重要作用，并为这种破坏性疾病提供了潜在的治疗靶标。
The median survival time of patients with glioblastoma is still poor (14.6 month), partly due to a lack of effective treatment. We have observed that androgen receptor (AR) is amplified in glioblastomas at the DNA, RNA and protein levels. The AR gene was amplified in 27% of glioblastoma specimens from men (n=22) and of 38.2% from women (n=21). AR-RNA was overexpressed (>2.5 fold) in 93% (n=30), and AR-protein was induced (>two fold) in 56% of the glioblastomas samples (n=16). Thirty percent of the glioblastomas (n=21) also expressed a constitutively active AR-splice-variant (AR-V7/AR3) lacking the Ligand-Binding-Domain. Following these findings, we examined the effect of pharmacological inhibition of androgen receptor in vitro and in vivo, as well as of genetic silencing of the receptor in glioblastoma cell lines. AR antagonists, induced concentration-dependent death in three glioblastoma cell lines, as well as in two glioma initiating cell lines. Silencing of AR expression by siRNA induced cell death in the three tested glioblastoma cell lines. Enzalutamide given orally to nude mice bearing subcutaneous human glioma xenografts resulted in a 72% reduction in tumor volume (p=0.0027). The presence of AR-V7/AR3 in glioblastoma, together with the present data showing that genetic silencing of the full length AR in cell lines and pharmacological inhibition of AR, induce GBM cell death in vivo and in vitro, point to the important role of AR in GBM survival and render a potential therapeutic target for this devastating disease.