Bone morphogenetic protein signaling mediated by ALK-2 and DLX2 regulates apoptosis in glioma-initiating cells.

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.

• Authors: E Raja, A Komuro, R Tanabe, S Sakai, Y Ino, N Saito, T Todo, M Morikawa, H Aburatani, D Koinuma, C Iwata, K Miyazono
• Journal: Oncogene (Oncogene) Vol. 36 Issue 35 Pg. 4963-4974 (08 31 2017) ISSN: 1476-5594 [Electronic] England
• PMID: 28459464 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bone Morphogenetic Proteins
• DLX2 protein, human
• Homeodomain Proteins
• Transcription Factors
• Valproic Acid
• ACVR1 protein, human
• Activin Receptors, Type I

Topics

• Activin Receptors, Type I (metabolism)
• Animals
• Apoptosis (drug effects, physiology)
• Bone Morphogenetic Proteins (metabolism)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Cell Differentiation (physiology)
• Female
• Glioma (drug therapy, metabolism, pathology)
• HEK293 Cells
• Heterografts
• Homeodomain Proteins (metabolism)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Phosphorylation
• Signal Transduction (drug effects)
• Transcription Factors (metabolism)
• Transfection
• Valproic Acid (pharmacology)