Abstract
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.
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Acknowledgements
We thank Y Kakiuchi for animal care. This work was supported by Grants-in-Aid for Scientific Research (KAKENHI 22112002) from the Ministry of Education, Culture, Sports and Technology of Japan (MEXT) and Scientific Research (B) and (S) (24390070 and 15H05774, respectively, KM) from the Japan Society for the Promotion of Science (JSPS), Grant-in-Aid from the Ministry of Health, Labour and Welfare of Japan (201220012C), the JSPS Core-to-Core Program 'Cooperative International Framework in TGF-β Family Signalling', and a grant from the Naito Foundation.
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Raja, E., Komuro, A., Tanabe, R. et al. Bone morphogenetic protein signaling mediated by ALK-2 and DLX2 regulates apoptosis in glioma-initiating cells. Oncogene 36, 4963–4974 (2017). https://doi.org/10.1038/onc.2017.112
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DOI: https://doi.org/10.1038/onc.2017.112
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