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

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...

Full description

Saved in:

Bibliographic Details
Published in:	Oncogene Vol. 34; no. 25; pp. 3305 - 3314
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 18-06-2015 Nature Publishing Group
Subjects:	13/105 13/106 13/31 13/51 13/89 13/95 14/1 14/19 631/67/1059/602 631/67/1922 64/60 Amino Acid Sequence Animals Apoptosis Astrocytoma Binding sites Brain cancer Cancer Cell Biology Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Cognition Cognition Disorders - complications Cognition Disorders - metabolism Cognition Disorders - prevention & control Cognitive ability Development and progression Female Gene Expression Regulation, Neoplastic - drug effects Genetic aspects Glioblastoma Glioblastoma - complications Glioblastoma - drug therapy Glioblastoma - pathology Glioblastoma - physiopathology Glioblastoma multiforme Growth Health aspects Heat shock proteins HSP70 Heat-Shock Proteins - genetics HSP70 Heat-Shock Proteins - metabolism Hsp70 protein HSP90 Heat-Shock Proteins - genetics HSP90 Heat-Shock Proteins - metabolism Hsp90 protein Human Genetics Humans Internal Medicine Kinases Male Medicine Medicine & Public Health Mice Mimicry Molecular Sequence Data Neoplasm Grading Nervous system Oncology original-article Peptide Fragments - chemistry Peptide Fragments - pharmacology Peptide Fragments - therapeutic use Peptides Prion protein Prions Prions - metabolism Protein Binding - drug effects Proteins Statistics Survival Analysis Tumors Xenograft Model Antitumor Assays
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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 (HOP 230–245 ) abrogates this effect. PrP C 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 PrP C –HOP engagement is a promising approach for GBM therapy.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2014.261