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

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.

authors

  • Lopes, MH
  • Santos, TG
  • Rodrigues, BR
  • Queiroz-Hazarbassanov, N
  • Cunha, IW
  • Wasilewska-Sampaio, AP
  • Costa-Silva, B
  • Marchi, FA
  • Bleggi-Torres, LF
  • Sanematsu, PI
  • Suzuki, SH
  • Oba-Shinjo, SM
  • Marie, SKN
  • Toulmin, E
  • Hill, AF
  • Martins, VR

publication date

  • 2015

has subject area