Abstract |
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 gamma-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 gamma-secretase inhibitors may have direct clinical application for the treatment of malignant glioma.
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Authors | LiMei Wang, Jennifer J Rahn, XueQing Lun, Beichen Sun, John J P Kelly, Samuel Weiss, Stephen M Robbins, Peter A Forsyth, Donna L Senger |
Journal | PLoS biology
(PLoS Biol)
Vol. 6
Issue 11
Pg. e289
(Nov 25 2008)
ISSN: 1545-7885 [Electronic] United States |
PMID | 19067488
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Enzyme Inhibitors
- Nerve Growth Factors
- Receptor, Nerve Growth Factor
- Recombinant Fusion Proteins
- Amyloid Precursor Protein Secretases
|
Topics |
- Amyloid Precursor Protein Secretases
(antagonists & inhibitors, metabolism)
- Animals
- Brain
(metabolism)
- Brain Neoplasms
(metabolism, therapy)
- Enzyme Inhibitors
(therapeutic use)
- Glioma
(metabolism, therapy)
- Humans
- Neoplasm Invasiveness
(physiopathology)
- Nerve Growth Factors
(metabolism)
- Receptor, Nerve Growth Factor
(metabolism)
- Recombinant Fusion Proteins
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