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Lopes M.H.,International Research Center | Lopes M.H.,University of Sao Paulo | Lopes M.H.,National Institute for Translational Neuroscience and National Institute of Oncogenomics | Santos T.G.,International Research Center | And 24 more authors.
Oncogene | Year: 2015

Glioblastomas (GBMs) are resistant to current therapy protocols and identification of molecules that target these tumors is crucial. Interaction of secreted heat-shock protein 70 (Hsp70)-Hsp90-organizing protein (HOP) with cellular prion protein (PrPC) triggers a large number of trophic effects in the nervous system. We found that both PrPC and HOP are highly expressed in human GBM samples relative to non-tumoral tissue or astrocytoma grades I-III. High levels of PrPC and HOP were associated with greater GBM proliferation and lower patient survival. HOP-PrPC binding increased GBM proliferation in vitro via phosphatidylinositide 3-kinase and extracellular-signal-regulated kinase pathways, and a HOP peptide mimicking the PrPC binding site (HOP 230-245) abrogates this effect. PrPC knockdown impaired tumor growth and increased survival of mice with tumors. In mice, intratumor delivery of HOP 230-245 peptide impaired proliferation and promoted apoptosis of GBM cells. In addition, treatment with HOP 230-245 peptide inhibited tumor growth, maintained cognitive performance and improved survival. Thus, together, the present results indicate that interfering with PrPC -HOP engagement is a promising approach for GBM therapy. © 2015 Macmillan Publishers Limited.

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