p75 neurotrophin receptor cleavage by α- and γ-secretases is required for neurotrophin-mediated proliferation of brain tumor-initiating cells.

Abstract

Malignant gliomas are highly invasive, proliferative, and resistant to treatment. Previously, we have shown that p75 neurotrophin receptor (p75NTR) is a novel mediator of invasion of human glioma cells. However, the role of p75NTR in glioma proliferation is unknown. Here we used brain tumor-initiating cells (BTICs) and show that BTICs express neurotrophin receptors (p75NTR, TrkA, TrkB, and TrkC) and their ligands (NGF, brain-derived neurotrophic factor, and neurotrophin 3) and secrete NGF. Down-regulation of p75NTR significantly decreased proliferation of BTICs. Conversely, exogenouous NGF stimulated BTIC proliferation through α- and γ-secretase-mediated p75NTR cleavage and release of its intracellular domain (ICD). In contrast, overexpression of the p75NTR ICD induced proliferation. Interestingly, inhibition of Trk signaling blocked NGF-stimulated BTIC proliferation and p75NTR cleavage, indicating a role of Trk in p75NTR signaling. Further, blocking p75NTR cleavage attenuated Akt activation in BTICs, suggesting role of Akt in p75NTR-mediated proliferation. We also found that p75NTR, α-secretases, and the four subunits of the γ-secretase enzyme were elevated in glioblastoma multiformes patients. Importantly, the ICD of p75NTR was commonly found in malignant glioma patient specimens, suggesting that the receptor is activated and cleaved in patient tumors. These results suggest that p75NTR proteolysis is required for BTIC proliferation and is a novel potential clinical target.

• Authors: Peter A Forsyth, Niveditha Krishna, Samuel Lawn, J Gerardo Valadez, Xiaotao Qu, David A Fenstermacher, Michelle Fournier, Lisa Potthast, Prakash Chinnaiyan, Geoffrey T Gibney, Michele Zeinieh, Philip A Barker, Bruce D Carter, Michael K Cooper, Rajappa S Kenchappa
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 12 Pg. 8067-85 (Mar 21 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24519935 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Growth Factors
• Receptor, Nerve Growth Factor
• Amyloid Precursor Protein Secretases

Topics

• Amyloid Precursor Protein Secretases (metabolism)
• Brain (metabolism, pathology)
• Brain Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Gene Knockdown Techniques
• Glioma (genetics, metabolism, pathology)
• Humans
• Mutation
• Neoplastic Stem Cells (cytology, metabolism, pathology)
• Nerve Growth Factors (metabolism)
• Receptor, Nerve Growth Factor (genetics, metabolism)