Role of cellular prion protein in temozolomide resistance of glioblastoma stem cells

Abstract Glioblastoma (GBM), the most aggressive type of brain tumor, is initiated and maintained by a subpopulation of tumorigenic cells called glioblastoma stem cells (GSCs) that contribute to progression and resistance to therapy. In GBM therapy the alkylating agent temozolomide (TMZ) is the most effective chemotherapist, but resistance is frequent, especially in GSCs located in hypoxia niches. One of the mechanisms of resistance to TMZ involves the modulation of MGMT, which promotes cell survival through the induction of antiapoptotic proteins expression and can be regulated by hypoxia inducible factors (HIFs). Recent data from our group demonstrate that blocking the interaction between the cellular prion protein (PrPC) and one of its main ligands, the heat shock organizing protein (HOP) with a HOP peptide (HOP230-245) can inhibit GSCs self-renewal and glioblastomas growth in vivo. PrPC silencing decreases the expression of stem cells markers, self-renewal, and tumorigenesis of GSCs. Remarkably, a PrPC peptide which mimics HOP binding site (PrPC106-126) can promote HIF1α expression, inducing protection against cell death. Considering these data together, this study aims to identify the participation of PrPC in the TMZ resistance of GSCs mediated by HIF1α. In addition, we will evaluate HOP230-245 peptide potential in sensitizing GSCs to TMZ, since it binds to PrPC at the specific site 106-126 being able to compete with other PrPC ligands by this domain and, consequently, inhibit functions modulated by these interactions. Preliminary trials on stem cell enriched glioblastoma lineage cultures suggest that treatment with TMZ associated HOP230-245 increases cell death compared to TMZ or the peptide alone, sensitizing cells to TMZ treatment and increasing their efficiency. Finally, the search for therapeutic-combined strategies targeting GSCs is imperative to improve the efficacy of treatments against this incurable tumor.