Arizona Health Sciences

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

TitleCRMP5 Controls Glioblastoma Cell Proliferation and Survival through Notch-Dependent Signaling.
Publication TypeJournal Article
Year of Publication2015
AuthorsMoutal A, Honnorat J, Massoma P, Désormeaux P, Bertrand C, Malleval C, Watrin C, Chounlamountri N, Mayeur M-E, Besançon R, Naudet N, Magadoux L, Khanna R, Ducray F, Meyronet D, Thomasset N
JournalCancer Res
Volume75
Issue17
Pagination3519-28
Date Published2015 Sep 1
ISSN1538-7445
KeywordsAdult, Aged, Aged, 80 and over, Animals, Brain Neoplasms, Cell Line, Tumor, Cell Proliferation, Female, Gene Expression Regulation, Neoplastic, Glioblastoma, Humans, Male, Mice, Middle Aged, Nerve Tissue Proteins, Receptors, Notch, Signal Transduction, Survival Analysis, Xenograft Model Antitumor Assays
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.

DOI10.1158/0008-5472.CAN-14-0631
Alternate JournalCancer Res.
PubMed ID26122847
Faculty Member Reference: 
Rajesh Khanna