Disruption of prion protein-HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival

作者：Lopes M H; Santos T G; Rodrigues B R; Queiroz Hazarbassanov N; Cunha I W; Wasilewska Sampaio A P; Costa Silva B; Marchi F A; Bleggi Torres L F; Sanematsu P I; Suzuki S H; Oba Shinjo S M; Marie S K N; Toulmin E; Hill A F; Martins V R^*

来源：Oncogene, 2015, 34(25): 3305-3314.

DOI：10.1038/onc.2014.261

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 (HOP230-245) abrogates this effect. PrPC knockdown impaired tumor growth and increased survival of mice with tumors. In mice, intratumor delivery of HOP230-245 peptide impaired proliferation and promoted apoptosis of GBM cells. In addition, treatment with HOP230-245 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.

• 出版日期2015-6