Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells

Abstract

Prion protein (PrPC) is a cell surface glycoprotein whose misfolding is responsible for prion diseases. Although its physiological role is not completely defined, several lines of evidence propose that PrPC is involved in self-renewal, pluripotency gene expression, proliferation and differentiation of neural stem cells. Moreover, PrPC regulates different biological functions in human tumors, including glioblastoma (GBM). We analyzed the role of PrPC in GBM cell pathogenicity focusing on tumor-initiating cells (TICs, or cancer stem cells, CSCs), the subpopulation responsible for development, progression and recurrence of most malignancies. Analyzing four GBM CSC-enriched cultures, we show that PrPC expression is directly correlated with the proliferation rate of the cells. To better define its role in CSC biology, we knocked-down PrPC expression in two of these GBM-derived CSC cultures by specific lentiviral-delivered shRNAs. We provide evidence that CSC proliferation rate, spherogenesis and in vivo tumorigenicity are significantly inhibited in PrPC down-regulated cells. Moreover, PrPC down-regulation caused loss of expression of the stemness and self-renewal markers (NANOG, Sox2) and the activation of differentiation pathways (i.e. increased GFAP expression). Our results suggest that PrPC controls the stemness properties of human GBM CSCs and that its down-regulation induces the acquisition of a more differentiated and less oncogenic phenotype.

Rapamycin promotes differentiation increasing βIII-tubulin, NeuN, and NeuroD while suppressing nestin expression in glioblastoma cells

“…However, recent evidence demonstrates that other mechanisms, such as the amount of prion protein, may strongly affect the phenotype of GBM cells [38]. Interestingly, rapamycin is able to modulate prion protein metabolism [39], which provides an alternative pathway for rapamycin induced phenotypic shift of GBM cells.…”

Inhibition of the Autophagy Pathway Synergistically Potentiates the Cytotoxic Activity of Givinostat (ITF2357) on Human Glioblastoma Cancer Stem Cells

“…All the cell cultures analyzed in this study were previously characterized for tumor-initiating capacity by orthotopic xenograft, induced by injection of 10,000 sphere-derived cells in 6–8-weeks old non-obese diabetic severe combined immunodeficient (NOD/SCID) mice (Charles River Laboratories, Wilminglon, MA, USA), as detailed in previous studies (Carra et al, 2013; Gritti et al, 2014; Corsaro et al, 2016). Animals were housed in pathogenic-free conditions, and handled in agreement with the institutional and national guidelines for the care and use of laboratory animals (Italian D.lgs 26/2014); the experimental plan was approved by the IRCCS AOU S. Martino-IST (Genova, Italy) Institutional Animal Care and Use Committee (IACUC).…”

Physiological Functions of the Cellular Prion Protein

“…Therefore, regulation of NSC proliferation by PrP C may be a consequence of its putative antioxidant properties or, conversely, protection from oxidative stress by PrP C may result from a role in regulating physiological production of ROS for signalling purposes. PrP C has also been observed to promote proliferation of colon adenocarcinoma cells (Chieng and Say, 2015), neuroblastoma cells (Llorens et al, 2013), cancer stem cells that give rise to glioblastoma (Corsaro et al, 2016), and precursor cells in intestinal organoid cultures (Besnier et al, 2015). In neuroblastoma cells, PrP C was proposed to interact with the epidermal growth factor receptor to promote activation of the PI3K-Akt pathway (Llorens et al, 2013).…”