Raja E, Komuro A, Tanabe R, Sakai S, Ino Y, Saito N, Todo T, Morikawa M, Aburatani H, Koinuma D, Iwata C, Miyazono K
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Division of Innovative Cancer Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Oncogene. 2017 Aug 31;36(35):4963-4974. doi: 10.1038/onc.2017.112. Epub 2017 May 1.
Bone morphogenetic protein (BMP) signaling exerts antitumor activities in glioblastoma; however, its precise mechanisms remain to be elucidated. Here, we demonstrated that the BMP type I receptor ALK-2 (encoded by the ACVR1 gene) has crucial roles in apoptosis induction of patient-derived glioma-initiating cells (GICs), TGS-01 and TGS-04. We also characterized a BMP target gene, Distal-less homeobox 2 (DLX2), and found that DLX2 promoted apoptosis and neural differentiation of GICs. The tumor-suppressive effects of ALK-2 and DLX2 were further confirmed in a mouse orthotopic transplantation model. Interestingly, valproic acid (VPA), an anti-epileptic compound, induced BMP2, BMP4, ACVR1 and DLX2 mRNA expression with a concomitant increase in phosphorylation of Smad1/5. Consistently, we showed that treatment with VPA induced apoptosis of GICs, whereas silencing of ALK-2 or DLX2 expression partially suppressed it. Our study thus reveals BMP-mediated inhibitory mechanisms for glioblastoma, which explains, at least in part, the therapeutic effects of VPA.
骨形态发生蛋白（BMP）信号传导在胶质母细胞瘤中发挥抗肿瘤活性；然而，其确切机制仍有待阐明。在此，我们证明了BMP I型受体ALK-2（由ACVR1基因编码）在诱导患者来源的胶质瘤起始细胞（GICs）TGS-01和TGS-04凋亡中起关键作用。我们还对一个BMP靶基因远端缺失同源盒2（DLX2）进行了表征，发现DLX2促进GICs的凋亡和神经分化。在小鼠原位移植模型中进一步证实了ALK-2和DLX2的肿瘤抑制作用。有趣的是，抗癫痫化合物丙戊酸（VPA）诱导BMP2、BMP4、ACVR1和DLX2 mRNA表达，同时伴随Smad1/5磷酸化增加。一致地，我们表明用VPA处理可诱导GICs凋亡，而沉默ALK-2或DLX2表达可部分抑制这种凋亡。因此，我们的研究揭示了BMP介导的胶质母细胞瘤抑制机制，这至少部分解释了VPA的治疗效果。
