BMP2 sensitizes glioblastoma stem-like cells to Temozolomide by affecting HIF-1α stability and MGMT expression

L. Persano, F. Pistollato, E. Rampazzo, A. Della Puppa, S. Abbadi, C. Frasson, F. Volpin, S. Indraccolo, R. Scienza, G. Basso

Research output: Contribution to journalArticle

Abstract

Glioblastoma multiforme (GBM) is the most common brain tumour, characterized by a central and partially necrotic (i.e., hypoxic) core enriched in cancer stem cells (CSCs). We previously showed that the most hypoxic and immature (i.e., CSCs) GBM cells were resistant to Temozolomide (TMZ) in vitro, owing to a particularly high expression of O6-methylguanine-DNAmethyltransferase (MGMT), the most important factor associated to therapy resistance in GBM. Bone morphogenetic proteins (BMPs), and in particular BMP2, are known to promote differentiation and growth inhibition in GBM cells. For this reason, we investigated whether a BMP2-based treatment would increase TMZ response in hypoxic drug-resistant GBM-derived cells. Here we show that BMP2 induced strong differentiation of GBM stem-like cells and subsequent addition of TMZ caused dramatic increase of apoptosis. Importantly, we correlated these effects to a BMP2-induced downregulation of both hypoxia-inducible factor-1α (HIF-1α) and MGMT. We report here a novel mechanism involving the HIF-1α-dependent regulation of MGMT, highlighting the existence of a HIF-1α/MGMT axis supporting GBM resistance to therapy. As confirmed from this evidence, overstabilization of HIF-1α in TMZ-sensitive GBM cells abolished their responsiveness to it. In conclusion, we describe a HIF-1αdependent regulation of MGMT and suggest that BMP2, by down-modulating the HIF-1α/MGMT axis, should increase GBM responsiveness to chemotherapy, thus opening the way to the development of future strategies for GBM treatment.

Original languageEnglish
Article numbere412
JournalCell Death and Disease
Volume3
Issue number10
DOIs
Publication statusPublished - Oct 2012

Keywords

  • BMP2
  • Glioblastoma
  • HIF-1α
  • Hypoxia
  • MGMT
  • Temozolomide

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'BMP2 sensitizes glioblastoma stem-like cells to Temozolomide by affecting HIF-1α stability and MGMT expression'. Together they form a unique fingerprint.

  • Cite this

    Persano, L., Pistollato, F., Rampazzo, E., Della Puppa, A., Abbadi, S., Frasson, C., Volpin, F., Indraccolo, S., Scienza, R., & Basso, G. (2012). BMP2 sensitizes glioblastoma stem-like cells to Temozolomide by affecting HIF-1α stability and MGMT expression. Cell Death and Disease, 3(10), [e412]. https://doi.org/10.1038/cddis.2012.153