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

Abstract

Prion protein (PrP^C) 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 PrP^C is involved in self-renewal, pluripotency gene expression, proliferation and differentiation of neural stem cells. Moreover, PrP^C regulates different biological functions in human tumors, including glioblastoma (GBM). We analyzed the role of PrP^C 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 PrP^C expression is directly correlated with the proliferation rate of the cells. To better define its role in CSC biology, we knocked-down PrP^C 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 PrP^C down-regulated cells. Moreover, PrP^C 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 PrP^C controls the stemness properties of human GBM CSCs and that its down-regulation induces the acquisition of a more differentiated and less oncogenic phenotype.