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Bone morphogenetic protein signaling mediated by ALK-2 and DLX2 regulates apoptosis in glioma-initiating cells.
Raja, E; Komuro, A; Tanabe, R; Sakai, S; Ino, Y; Saito, N; Todo, T; Morikawa, M; Aburatani, H; Koinuma, D; Iwata, C; Miyazono, K.
Afiliación
  • Raja E; Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Komuro A; Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Tanabe R; Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Sakai S; Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Ino Y; Division of Innovative Cancer Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • Saito N; Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Todo T; Division of Innovative Cancer Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • Morikawa M; Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Aburatani H; Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan.
  • Koinuma D; Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Iwata C; Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Miyazono K; Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Oncogene ; 36(35): 4963-4974, 2017 08 31.
Article en En | MEDLINE | ID: mdl-28459464
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Células Madre Neoplásicas / Neoplasias Encefálicas / Ácido Valproico / Proteínas de Homeodominio / Proteínas Morfogenéticas Óseas / Receptores de Activinas Tipo I / Glioma Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2017 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Células Madre Neoplásicas / Neoplasias Encefálicas / Ácido Valproico / Proteínas de Homeodominio / Proteínas Morfogenéticas Óseas / Receptores de Activinas Tipo I / Glioma Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2017 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido