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

Author(s):Show less -

Lopes, M. H. ^{[1, 2, 3, 4]} ; Santos, T. G. ^{[2, 3, 4]} ; Rodrigues, B. R. ^{[2, 3, 4]} ; Queiroz-Hazarbassanov, N. ^{[2, 3, 4]} ; Cunha, I. W. ^[5] ; Wasilewska-Sampaio, A. P. ^{[2, 3, 4]} ; Costa-Silva, B. ^{[2, 3, 4]} ; Marchi, F. A. ^{[2, 3, 4, 6]} ; Bleggi-Torres, L. F. ^{[7, 8]} ; Sanematsu, P. I. ^[9] ; Suzuki, S. H. ^[9] ; Oba-Shinjo, S. M. ^[10] ; Marie, S. K. N. ^[10] ; Toulmin, E. ^[11] ; Hill, A. F. ^[11] ; Martins, V. R. ^{[12, 2, 3, 4]}

Affiliation:Show less -

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Cell & Dev Biol, Sao Paulo - Brazil

^[2] AC Camargo Canc Ctr, Int Res Ctr, BR-01508010 Sao Paulo - Brazil

^[3] CNPq MCT FAPESP, Nat Inst Translat Neurosci, Sao Paulo - Brazil

^[4] CNPq MCT FAPESP, Natl Inst Oncogen, Sao Paulo - Brazil

^[5] AC Camargo Canc Ctr, Dept Pathol, BR-01508010 Sao Paulo - Brazil

^[6] Univ Sao Paulo, Inst Math & Stat, Interinst Grad Program Bioinformat, Sao Paulo - Brazil

^[7] Univ Fed Parana, Dept Pathol, BR-80060000 Curitiba, Parana - Brazil

^[8] Pele Pequeno Principe Res Inst, Curitiba, Parana - Brazil

^[9] AC Camargo Canc Ctr, Dept Neurosurg, BR-01508010 Sao Paulo - Brazil

^[10] Univ Sao Paulo, Sch Med, Dept Neurol, BR-05508 Sao Paulo - Brazil

^[11] Univ Melbourne, Dept Biochem & Mol Biol, Mol Sci & Biotechnol Inst Bio21, Melbourne, Vic - Australia

^[12] Ludwig Inst Canc Res, Sao Paulo - Brazil

• Document type: Journal article
• Source: Oncogene; v. 34, n. 25, p. 3305-3314, JUN 2015.
• Web of Science Citations: 12

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 (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. (AU)

• FAPESP's process: 07/08410-2 - Role of the STI1-PrPc interaction in the biology of neural stem cells: physiological and tumoral contexts
• Grantee: Marilene Hohmuth Lopes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/19019-0 - Regulation of STAT3 activity and the role of secreted STI1/Hop protein in glioblastoma multiforme
• Grantee: Bruna Roz Rodrigues
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 09/14027-2 - Mechanisms associated with the function of prion protein and its ligand STI1/Hop: therapeutic approaches
• Grantee: Vilma Regina Martins
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 04/12133-6 - Search for molecular markers related to the diagnosis and prognosis of tumors of the central nervous system
• Grantee: Suely Kazue Nagahashi Marie
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/20796-6 - Prion protein and its STI1 ligands and laminin: possible implications in Alzheimer's Disease
• Grantee: Ana Paula Wasilewska Sampaio
• Support Opportunities: Scholarships in Brazil - Post-Doctoral