title: PDGFRα depletion attenuates glioblastoma stem cells features by modulation of STAT3, RB1 and multiple oncogenic signals.
abstract: Platelet derived growth factor receptors (PDGFRs) play an important role in tumor pathogenesis, and they are frequently overexpressed in glioblastoma (GBM). Earlier we have shown a higher protein expression of PDGFR isoforms (α and β) in peritumoral-tissue derived cancer stem cells (p-CSC) than in tumor core (c-CSC) of several GBM affected patients. In the current study, in order to assess the activity of PDGFRα/PDGF-AA signaling axis, we performed time course experiments to monitor the effects of exogenous PDGF-AA on the expression of downstream target genes in c-CSC vs p-CSC. Interestingly, in p-CSC we detected the upregulation of Y705-phosphorylated Stat3, concurrent with a decrement of Rb1 protein in its active state, within minutes of PDGF-AA addition. This finding prompted us to elucidate the role of PDGFRα in self-renewal, invasion and differentiation in p-CSC by using short hairpin RNA depletion of PDGFRα expression. Notably, in PDGFRα-depleted cells, protein analysis revealed attenuation of stemness-related and glial markers expression, alongside early activation of the neuronal marker MAP2a/b that correlated with the induction of tumor suppressor Rb1. The in vitro reduction of the invasive capacity of PDGFRα-depleted CSC as compared to parental cells correlated with the downmodulation of markers of epithelial-mesenchymal transition phenotype and angiogenesis. Surprisingly, we observed the induction of anti-apoptotic proteins and compensatory oncogenic signals such as EDN1, EDNRB, PRKCB1, PDGF-C and PDGF-D. To conclude, we hypothesize that the newly discovered PDGFRα/Stat3/Rb1 regulatory axis might represent a potential therapeutic target for GBM treatment.
authors.affiliation: Institute of Translational Pharmacology, Department of Biomedical Sciences-National Research Council (IFT-CNR), Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Cenciarelli
authors.affiliation: Biomedical Research Center, Qatar University, Doha, Qatar.
authors.forename: Hany E
authors.initials: HE
authors.lastname: Marei
authors.affiliation: Institute of Cell Biology and Neurobiology, Dept. of Biomedical Sciences-National Research Council (IBCN-CNR), Rome, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Felsani
authors.affiliation: Institute of Cell Biology and Neurobiology, Dept. of Biomedical Sciences-National Research Council (IBCN-CNR), Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casalbore
authors.affiliation: Institute of Histology and Embryology, Catholic University-School of Medicine, Rome, Italy.
authors.forename: Gigliola
authors.initials: G
authors.lastname: Sica
authors.affiliation: Department of Internal Medicine and Gastroenterology, Agostino Gemelli Hospital, Rome, Italy.
authors.forename: Maria Ausiliatrice
authors.initials: MA
authors.lastname: Puglisi
authors.affiliation: Barts Cancer Institute, John Vane Science Centre, Queen Mary University of London, London, United Kingdom.
authors.forename: Angus J M
authors.initials: AJ
authors.lastname: Cameron
authors.affiliation: Institute of Neurosurgery, Department of Head and Neck, Catholic University-School of Medicine, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Olivi
authors.affiliation: Institute of Neurosurgery, Department of Head and Neck, Catholic University-School of Medicine, Rome, Italy.
authors.forename: Annunziato
authors.initials: A
authors.lastname: Mangiola
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D034622:RNA Interference; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D056286:Retinoblastoma Binding Proteins / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D010982:Platelet-Derived Growth Factor; C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; D050796:STAT3 Transcription Factor; C075278:platelet-derived growth factor A; D044767:Ubiquitin-Protein Ligases; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: PDGFRα; RB1; STAT3; cancer stem cells; glioblastoma