Abstract 4400: The levels of Prion protein and its ligand HOP modulate glioblastoma proliferation and predict a lower survival outcome.
Authors: Lopes Marilene H. , Queiroz Nicole Gilda , Santos Tiago Goss , Rodrigues Bruna R. , Cunha Isabela W. , Silva Bruno Costa , Martins Vilma R. 
Published: August 2014

A main concern in glioblastoma (GBM) therapy is the resistance of these tumors to current treatment protocols. The identification of molecules that can be target to treat these tumors is of major interest. The prion protein (PrPC) is a glycosylphosphatidylinositol-anchored protein very abundant in neurons and astrocytes and its interaction with a diverse number of ligands modulates cell survival and differentiation. One of these ligands is the secreted co-chaperone Hsp70-Hsp90 organizing protein (HOP), which reaches the extracellular space in exosome-like microvesicles. HOP is secreted by a number of cancer cells and seems to be a relevant biomarker in ovarian tumors. However, the role of PrPC-HOP complex in tumor biology is largely unknown. Herein, 185 cases o gliomas (33 grade I, 46 grade II, 15 grade II and 91 GBM) arranged in tissue microarrays were evaluated for the expression of PrPC and its ligand HOP. Both proteins were highly expressed in GBM when compared to tumors of grade I, II or III and also when compared to non-tumor samples (p&lt;0.05 for all comparisons). High expression levels of both proteins in GBMs were direct correlated with a higher tumor proliferation, measured by the number of cells positive for Ki-67. Patients with high levels of both proteins presented a lower survival than those with high levels of HOP but lower levels of PrPC (p=0.017). The treatment of a human GBM cell line U87MG, which presents high expression of PrPC, with soluble HOP increases proliferation by three times however any effect was observed when cells were treated with a soluble HOP lacking the PrPC binding site (HOPΔ230-245). Both HOP or HOPΔ230-245 have no effect in U87MG cells whose PrPC expression was knocked down by 98%. In accordance, the intra-tumor infusion of HOP, but not HOPΔ230-245, increased tumor growth in nude mice bearing U87MG orthotopic xenografts. Remarkably, U87MG cells in which PrPC expression was knocked down were unable to growth tumors in nude mice. Together these results demonstrated that PrPC and HOP are significantly expressed in GBMs and higher levels of these proteins are associated to the patient group presenting a lower survival. The manipulation of PrPC and HOP interaction in cell cultures or in vivo affects tumor growth indicating that the interference with their engagement may represent a therapeutic target in GBMs.

Supported by The State of São Paulo Foundation.

Citation Format: Marilene H. Lopes, Nicole Gilda Queiroz, Tiago Goss Santos, Bruna R. Rodrigues, Isabela W. Cunha, Bruno Costa Silva, Vilma R. Martins. The levels of Prion protein and its ligand HOP modulate glioblastoma proliferation and predict a lower survival outcome. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4400. doi:10.1158/1538-7445.AM2013-4400