Research Papers:

The interference of Notch1 target Hes1 affects cell growth, differentiation and invasiveness of glioblastoma stem cells through modulation of multiple oncogenic targets

Carlo Cenciarelli _, Hany E. Marei, Manuela Zonfrillo, Patrizia Casalbore, Armando Felsani, Stefano Giannetti, Gianluca Trevisi, Asma Althani and Annunziato Mangiola

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Oncotarget. 2017; 8:17873-17886. https://doi.org/10.18632/oncotarget.15013

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Carlo Cenciarelli1, Hany E. Marei2, Manuela Zonfrillo1, Patrizia Casalbore3, Armando Felsani3, Stefano Giannetti4, Gianluca Trevisi5, Asma Althani2, Annunziato Mangiola5

1Institute of Translational Pharmacology (IFT), National Research Council (CNR), Roma, Italy

2Biomedical Research Center, Qatar University, Doha, Qatar

3Institute of Cell Biology and Neurobiology (IBCN), National Research Council (CNR), Roma, Italy

4Institute of Anatomy and Cell Biology, Catholic University-School of Medicine, Roma, Italy

5Department of Head and Neck, Institute of Neurosurgery, Catholic University-School of Medicine, Roma, Italy

Correspondence to:

Carlo Cenciarelli, email: carlo.cenciarelli@ift.cnr.it

Keywords: glioblastoma stem cells, Notch1, Hes1, self-renewal, differentiation

Received: December 27, 2016     Accepted: January 25, 2017     Published: February 02, 2017


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.

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