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Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor

The multifunctional signaling protein p75 neurotrophin receptor (p75(NTR)) is a central regulator and major contributor to the highly invasive nature of malignant gliomas. Here, we show that neurotrophin-dependent regulated intramembrane proteolysis (RIP) of p75(NTR) is required for p75(NTR)-mediate...

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Autores principales: Wang, LiMei, Rahn, Jennifer J, Lun, XueQing, Sun, Beichen, Kelly, John J. P, Weiss, Samuel, Robbins, Stephen M, Forsyth, Peter A, Senger, Donna L
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2586378/
https://www.ncbi.nlm.nih.gov/pubmed/19067488
http://dx.doi.org/10.1371/journal.pbio.0060289
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author Wang, LiMei
Rahn, Jennifer J
Lun, XueQing
Sun, Beichen
Kelly, John J. P
Weiss, Samuel
Robbins, Stephen M
Forsyth, Peter A
Senger, Donna L
author_facet Wang, LiMei
Rahn, Jennifer J
Lun, XueQing
Sun, Beichen
Kelly, John J. P
Weiss, Samuel
Robbins, Stephen M
Forsyth, Peter A
Senger, Donna L
author_sort Wang, LiMei
collection PubMed
description The multifunctional signaling protein p75 neurotrophin receptor (p75(NTR)) is a central regulator and major contributor to the highly invasive nature of malignant gliomas. Here, we show that neurotrophin-dependent regulated intramembrane proteolysis (RIP) of p75(NTR) is required for p75(NTR)-mediated glioma invasion, and identify a previously unnamed process for targeted glioma therapy. Expression of cleavage-resistant chimeras of p75(NTR) or treatment of animals bearing p75(NTR)-positive intracranial tumors with clinically applicable γ-secretase inhibitors resulted in dramatically decreased glioma invasion and prolonged survival. Importantly, proteolytic processing of p75(NTR) was observed in p75(NTR)-positive patient tumor specimens and brain tumor initiating cells. This work highlights the importance of p75(NTR) as a therapeutic target, suggesting that γ-secretase inhibitors may have direct clinical application for the treatment of malignant glioma.
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spelling pubmed-25863782008-11-25 Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor Wang, LiMei Rahn, Jennifer J Lun, XueQing Sun, Beichen Kelly, John J. P Weiss, Samuel Robbins, Stephen M Forsyth, Peter A Senger, Donna L PLoS Biol Research Article The multifunctional signaling protein p75 neurotrophin receptor (p75(NTR)) is a central regulator and major contributor to the highly invasive nature of malignant gliomas. Here, we show that neurotrophin-dependent regulated intramembrane proteolysis (RIP) of p75(NTR) is required for p75(NTR)-mediated glioma invasion, and identify a previously unnamed process for targeted glioma therapy. Expression of cleavage-resistant chimeras of p75(NTR) or treatment of animals bearing p75(NTR)-positive intracranial tumors with clinically applicable γ-secretase inhibitors resulted in dramatically decreased glioma invasion and prolonged survival. Importantly, proteolytic processing of p75(NTR) was observed in p75(NTR)-positive patient tumor specimens and brain tumor initiating cells. This work highlights the importance of p75(NTR) as a therapeutic target, suggesting that γ-secretase inhibitors may have direct clinical application for the treatment of malignant glioma. Public Library of Science 2008-11 2008-11-25 /pmc/articles/PMC2586378/ /pubmed/19067488 http://dx.doi.org/10.1371/journal.pbio.0060289 Text en © 2008 Wang et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wang, LiMei
Rahn, Jennifer J
Lun, XueQing
Sun, Beichen
Kelly, John J. P
Weiss, Samuel
Robbins, Stephen M
Forsyth, Peter A
Senger, Donna L
Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor
title Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor
title_full Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor
title_fullStr Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor
title_full_unstemmed Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor
title_short Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor
title_sort gamma-secretase represents a therapeutic target for the treatment of invasive glioma mediated by the p75 neurotrophin receptor
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2586378/
https://www.ncbi.nlm.nih.gov/pubmed/19067488
http://dx.doi.org/10.1371/journal.pbio.0060289
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