The interference of Notch1 target Hes1 affects cell growth, differentiation and invasiveness of glioblastoma stem cells through modulation of multiple oncogenic targets.
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.
Institute of Translational Pharmacology (IFT), National Research Council (CNR), Roma, Italy.
Carlo
C
Cenciarelli
Biomedical Research Center, Qatar University, Doha, Qatar.
Hany E
HE
Marei
Institute of Translational Pharmacology (IFT), National Research Council (CNR), Roma, Italy.
Manuela
M
Zonfrillo
Institute of Cell Biology and Neurobiology (IBCN), National Research Council (CNR), Roma, Italy.
Patrizia
P
Casalbore
Institute of Cell Biology and Neurobiology (IBCN), National Research Council (CNR), Roma, Italy.
Armando
A
Felsani
Institute of Anatomy and Cell Biology, Catholic University-School of Medicine, Roma, Italy.
Stefano
S
Giannetti
Department of Head and Neck, Institute of Neurosurgery, Catholic University-School of Medicine, Roma-Italy.
Gianluca
G
Trevisi
Biomedical Research Center, Qatar University, Doha, Qatar.
Asma
A
Althani
Department of Head and Neck, Institute of Neurosurgery, Catholic University-School of Medicine, Roma-Italy.
Annunziato
A
Mangiola
D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002219:Carbamates / Q000494:pharmacology; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004151:Dipeptides / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051881:Receptor, Notch1 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072056:Transcription Factor HES-1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001562:Benzimidazoles; D002219:Carbamates; D004151:Dipeptides; C410009:L 685458; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; C497761:NOTCH1 protein, human; D010880:Piperidines; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D000072056:Transcription Factor HES-1; D025521:Tumor Suppressor Proteins; C078493:HES1 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C577197:crenolanib
Hes1; Notch1; differentiation; glioblastoma stem cells; self-renewal