Disruption of Prion protein-HOP Engagement Impairs Glioblastoma Growth and Cognitive Decline and Improves Overall Survival

Oncogene. 2015 Jun;34(25):3305-14. doi: 10.1038/onc.2014.261. Epub 2014 Aug 25.

Abstract

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 (PrP(C)) triggers a large number of trophic effects in the nervous system. We found that both PrP(C) and HOP are highly expressed in human GBM samples relative to non-tumoral tissue or astrocytoma grades I-III. High levels of PrP(C) and HOP were associated with greater GBM proliferation and lower patient survival. HOP-PrP(C) binding increased GBM proliferation in vitro via phosphatidylinositide 3-kinase and extracellular-signal-regulated kinase pathways, and a HOP peptide mimicking the PrP(C) binding site (HOP230-245) abrogates this effect. PrP(C) 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 PrP(C)-HOP engagement is a promising approach for GBM therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cognition Disorders / complications
  • Cognition Disorders / metabolism
  • Cognition Disorders / prevention & control*
  • Cognition*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / complications
  • Glioblastoma / drug therapy
  • Glioblastoma / pathology*
  • Glioblastoma / physiopathology*
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism*
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Male
  • Mice
  • Molecular Sequence Data
  • Neoplasm Grading
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology
  • Peptide Fragments / therapeutic use
  • Prions / metabolism*
  • Protein Binding / drug effects
  • Survival Analysis
  • Xenograft Model Antitumor Assays

Substances

  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Peptide Fragments
  • Prions