Abstract
The invasive and lethal nature of Glioblastoma multiforme (GBM) necessitates the continuous identification of molecular targets and search of efficacious therapies to inhibit GBM growth. The GBM resistance to chemotherapy and radiation it is attributed to the existence of a rare fraction of cancer stem cells (CSC) that we have identified within the tumor core and in peritumor tissue of GBM. Since Notch1 pathway is a potential therapeutic target in brain cancer, earlier we highlighted that pharmacological inhibition of Notch1 signalling by γ-secretase inhibitor-X (GSI-X), reduced cell growth of some c-CSC than to their respective p-CSC, but produced negligible effects on cell cycle distribution, apoptosis and cell invasion. In the current study, we assessed the effects of Hes1-targeted shRNA, a Notch1 gene target, specifically on GBM CSC refractory to GSI-X. Depletion of Hes1 protein induces major changes in cell morphology, cell growth rate and in the invasive ability of shHes1-CSC in response to growth factor EGF. shHes1-CSC show a decrease of the stemness marker Nestin concurrently to a marked increase of neuronal marker MAP2 compared to pLKO.1-CSC. Those effects correlated with repression of EGFR protein and modulation of Stat3 phosphorylation at Y705 and S727 residues. In the last decade Stat3 has gained attention as therapeutic target in cancer but there is not yet any approved Stat3-based glioma therapy. Herein, we report that exposure to a Stat3/5 inhibitor, induced apoptosis either in shHes1-CSC or control cells. Taken together, Hes1 seems to be a favorable target but not sufficient itself to target GBM efficaciously, therefore a possible pharmacological intervention should provide for the use of anti-Stat3/5 drugs either alone or in combination regimen.
Highlights
Among the different types of brain tumors, glioblastoma multiforme (GBM) is the most aggressive and recurrent one
We investigated the effects of depletion of Hes1 expression, as one of the main target gene of Notch signaling, on the modulation of cell growth, differentiation, invasive ability and apoptosis of Glioblastoma multiforme (GBM) cancer stem cells (CSC)
As Notch1 is known to be a regulator for neurogenesis and plays crucial role in other cell fate decisions, our study clearly showed the upregulation of neuronal and glial markers MAP2 and GFAP respectively, and repression of β-TubIII and Nestin proteins in shHes1-CSC vs pLKO.1-CSC (Figure 1B)
Summary
Among the different types of brain tumors, glioblastoma multiforme (GBM) is the most aggressive and recurrent one. The Cancer Genome Atlas (TCGA) proposed a gene expression-based classification of GBM: classical/ EGFR+, proneural/PDGFR +, and mesenchymal/NF1+ [2, 3]. Such a classification has been crucial to explain the biology and the heterogeneous nature of GBM, but its prognostic value was rather limited. Fifty percent of all GBM tumors present in the TCGA can be classified into high miR-21/low Sox or low miR-21/high Sox subtypes [4] This classification can predict patient survival better than the currently used parameters. It has been reported that MLK4 dependent-NF-κB activation induced a mesenchymal trans-differentiation and radio-resistance in GBM CSC, assigning to MLK4-NF-κB signaling axis a potential prognostic value useful for GBM with a mesenchymal signature [7, 8]
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