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.
Highlights
Among the different types of adult brain tumors, glioblastoma multiforme (GBM) is the most aggressive and angiogenic, but despite the efforts to find effective treatments, these tumors remain incurable [1]
We noted a tight correlation between this phosphorylation event and the transient decrement of the tumor suppressor Rb1 in its active state, that occurred within 10 minutes, as detected by a monoclonal antibody that recognizes hypophosphorylated active Rb1
Our work aimed to assess the role of PDGFRα signaling in self-renewal, differentiation, invasion and epithelial-mesenchymal transition (EMT) phenotype in glioblastoma CSC through the knockdown of PDGFRα expression
Summary
Among the different types of adult brain tumors, glioblastoma multiforme (GBM) is the most aggressive and angiogenic, but despite the efforts to find effective treatments, these tumors remain incurable [1]. Platelet-derived growth factors (PDGFs) isoforms and receptors (PDGFRs) have important functions in the regulation of growth and survival of certain cell types during embryonal development and in control of tissue homeostasis in the adult [5]. Over-activity of PDGF signaling is associated with tumor development in brain, prostate, liver, lung, leukemia and colon cancers [7, 8]. Ligand-induced dimerization favors autophosphorylation of specific tyrosine residues and subsequent activates downstream signal pathways: PI3K/Akt1/mTOR, Ras/MAPK, PLC-γ/PKC and STAT3. PDGFR binds and activates signal transducers and activator of transcription (STATs). Stat has been implicated in the self-renewal of neural stem cells and glial differentiation while restricting neuronal differentiation [8,9,10,11,12,13]
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