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

E Raja1, A Komuro1, R Tanabe1

  • 1Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Oncogene
|May 2, 2017
PubMed

Insights

Bone morphogenetic protein (BMP) signaling inhibits glioblastoma by inducing apoptosis in glioma-initiating cells (GICs) via ALK-2 and DLX2. The anti-epileptic drug valproic acid (VPA) activates this pathway, offering therapeutic potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Neuroscience

Background:

  • Bone morphogenetic protein (BMP) signaling is implicated in glioblastoma (GBM) but its precise antitumor mechanisms require elucidation.
  • Glioma-initiating cells (GICs) are key drivers of GBM, and understanding their regulation is critical for developing effective therapies.

Purpose of the Study:

  • To investigate the role of BMP signaling, specifically the ALK-2 receptor and its target gene DLX2, in GIC apoptosis and neural differentiation.
  • To explore the therapeutic potential of valproic acid (VPA) in modulating BMP signaling for glioblastoma treatment.

Main Methods:

  • Utilized patient-derived GICs (TGS-01 and TGS-04) to study apoptosis and differentiation.
  • Employed a mouse orthotopic transplantation model to validate tumor-suppressive effects in vivo.
  • Analyzed gene expression (mRNA) and protein phosphorylation (Smad1/5) in response to VPA treatment.
  • Investigated the effects of VPA on GICs, including ALK-2 and DLX2 silencing.

Main Results:

  • BMP type I receptor ALK-2 (ACVR1) is crucial for inducing apoptosis in GICs.
  • BMP target gene Distal-less homeobox 2 (DLX2) promotes GIC apoptosis and neural differentiation.
  • Tumor-suppressive effects of ALK-2 and DLX2 were confirmed in vivo.
  • Valproic acid (VPA) upregulates BMP2, BMP4, ACVR1, and DLX2, activating Smad1/5 phosphorylation and inducing GIC apoptosis.
  • Silencing ALK-2 or DLX2 partially abrogated VPA-induced GIC apoptosis.

Conclusions:

  • BMP signaling, mediated by ALK-2 and DLX2, exerts tumor-suppressive effects in glioblastoma by promoting GIC apoptosis and differentiation.
  • Valproic acid (VPA) activates BMP signaling, explaining its therapeutic efficacy against glioblastoma.
  • This study elucidates novel BMP-driven mechanisms against glioblastoma and highlights VPA as a potential therapeutic agent.

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