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The response to the growth inhibitory activity of bone morphogenetic protein 4 in human glioblastoma cell lines is heterogeneous and dependent on SOX2

ABSTRACT: Glioblastoma multiforme (GBM) continues to have a dismal prognosis. Even though detailed information on the genetic aberrations in cell signaling and cell cycle checkpoint control is available, no effective targeted treatment has been developed. Despite the advanced molecular defects, glioblastoma cells may have remnants of normal growth inhibitory pathways, such as the bone morphogenetic protein (BMP) signaling pathway. We have evaluated the growth inhibitory effect of bone morphogenetic protein 4 (BMP4) across a broad spectrum of patient samples, using a panel of 40 human glioblastoma initiating cell (GIC) cultures. A wide range of responsiveness was observed. BMP4 response was positively correlated with a proneural mRNA expression profile, high SOX2 activity, and BMP4-dependent upregulation of genes associated with inhibition of the MAPK pathway, as demonstrated by gene set enrichment analysis (GSEA). BMP4 response in sensitive cells was mediated by the canonical BMP receptor pathway involving SMAD1/5 phosphorylation and SMAD4 expression. SOX2 was consistently down regulated in BMP4-treated cells. Forced expression of SOX2 attenuated the BMP4 response including a reduced upregulation om MAPK inhibitory genes, implying a functional relationship between SOX2 down regulation and responsiveness. The results show an extensive heterogeneity in BMP4 responsiveness among GICs, and identify a BMP4 sensitive subgroup, in which SOX2 is a mediator of the response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143934 | GEO | 2020/01/21

REPOSITORIES: GEO

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