CRMP5 Controls Glioblastoma Cell Proliferation and Survival through Notch-Dependent Signaling.

Abstract

Collapsin response mediator protein 5 (CRMP5) belongs to a family of five cytosolic proteins that play a major role in nervous system development. This protein was first described in cancer-induced autoimmune processes, causing neurodegenerative disorders (paraneoplastic neurologic syndromes). CRMP5 expression has been reported to serve as a biomarker for high-grade lung neuroendocrine carcinomas; however, its functional roles have not been examined in any setting of cancer pathophysiology. In this study, we report two different CRMP5 expression patterns observed in human glioblastoma (GBM) biopsies that establish connections between CRMP5 expression, Notch receptor signaling, and GBM cell proliferation. We demonstrated that elevated CRMP5 promotes Notch receptor expression and Akt activation in human tumor cell lines, GBM stem cells, and primary tumor biopsies. We have shown that the high CRMP5 and Notch expression in GBM xenograft is related to stem cells. This suggests that high CRMP5 expression pattern in GBM biopsies encompasses a subset of stem cells. Mechanistically, CRMP5 functioned by hijacking Notch receptors from Itch-dependent lysosomal degradation. Our findings suggest that CRMP5 serves as a major mediator of Notch signaling and Akt activation by controlling the degradation of the Notch receptor, with implications for defining a biomarker signature in GBM that correlates with and may predict patient survival.

• Authors: Aubin Moutal, Jérôme Honnorat, Patrick Massoma, Pauline Désormeaux, Caroline Bertrand, Céline Malleval, Chantal Watrin, Naura Chounlamountri, Marie-Eve Mayeur, Roger Besançon, Nicolas Naudet, Léa Magadoux, Rajesh Khanna, François Ducray, David Meyronet, Nicole Thomasset
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 17 Pg. 3519-28 (Sep 01 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 26122847 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Microtubule-Associated Proteins
• Nerve Tissue Proteins
• Receptors, Notch
• DPYSL5 protein, human
• Hydrolases

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Brain Neoplasms (genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Glioblastoma (genetics, pathology)
• Humans
• Hydrolases
• Male
• Mice
• Microtubule-Associated Proteins
• Middle Aged
• Nerve Tissue Proteins (biosynthesis, genetics)
• Receptors, Notch (genetics, metabolism)
• Signal Transduction
• Survival Analysis
• Xenograft Model Antitumor Assays