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Engagement of cellular prion protein with the co-chaperone Hsp70/90 organizing protein regulates the proliferation of glioblastoma stem-like cells


Background: Glioblastoma (GBM), a highly aggressive brain tumor, contains a subpopulation of glioblastomastem-like cells (GSCs) that play roles in tumor maintenance, invasion, and therapeutic resistance. GSCs are thereforea promising target for GBM treatment. Our group identified the cellular prion protein (PrPC) and its partner, theco-chaperone Hsp70/90 organizing protein (HOP), as potential target candidates due to their role in GBMtumorigenesis and in neural stem cell maintenance.Methods: GSCs expressing different levels of PrPC were cultured as neurospheres with growth factors, andcharacterized with stem cells markers and adhesion molecules markers through immunofluorescence and flowcytometry. We than evaluated GSC self-renewal and proliferation by clonal density assays and BrdU incorporation,respectively, in front of recombinant HOP treatment, combined or not with a HOP peptide which mimics the PrPCbinding site. Stable silencing of HOP was also performed in parental and/or PrPC-depleted cell populations, andproliferation in vitro and tumor growth in vivo were evaluated. Migration assays were performed on laminin-1pre-coated glass.Results: We observed that, when GBM cells are cultured as neurospheres, they express specific stemness markerssuch as CD133, CD15, Oct4, and SOX2; PrPC is upregulated compared to monolayer culture and co-localizes withCD133. PrPC silencing downregulates the expression of molecules associated with cancer stem cells, upregulatesmarkers of cell differentiation and affects GSC self-renewal, pointing to a pivotal role for PrPC in the maintenance ofGSCs. Exogenous HOP treatment increases proliferation and self-renewal of GSCs in a PrPC-dependent mannerwhile HOP knockdown disturbs the proliferation process. In vivo, PrPC and/or HOP knockdown potently inhibits thegrowth of subcutaneously implanted glioblastoma cells. In addition, disruption of the PrPC-HOP complex by a HOPpeptide, which mimics the PrPC binding site, affects GSC self-renewal and proliferation indicating that the HOP-PrPCcomplex is required for GSC stemness. Furthermore, PrPC-depleted GSCs downregulate cell adhesion-relatedproteins and impair cell migration indicating a putative role for PrPC in the cell surface stability of cell adhesionmolecules and GBM cell invasiveness, respectively. (AU)

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