CRMP2 Phosphorylation Drives Glioblastoma Cell Proliferation.

Abstract

Glioblastoma (GBM) is an aggressive primary brain tumor. The rapid growth and the privileged provenance of the tumor within the brain contribute to its aggressivity and poor therapeutic targeting. A poor prognostic factor in glioblastoma is the deletion or mutation of the Nf1 gene. This gene codes for the protein neurofibromin, a tumor suppressor gene that is known to interact with the collapsin response mediator protein 2 (CRMP2). CRMP2 expression and elevated expression of nuclear phosphorylated CRMP2 have recently been implicated in cancer progression. The CRMP2-neurofibromin interaction protects CRMP2 from its phosphorylation by cyclin-dependent kinase 5 (Cdk5), an event linked to cancer progression. In three human glioblastoma cell lines (GL15, A172, and U87), we observed an inverse correlation between neurofibromin expression and CRMP2 phosphorylation levels. Glioblastoma cell proliferation was dependent on CRMP2 expression and phosphorylation by Cdk5 and glycogen synthase kinase 3 beta (GSK3β). The CRMP2 phosphorylation inhibitor (S)-lacosamide reduces, in a concentration-dependent manner, glioblastoma cell proliferation and induced apoptosis in all three GBM cell lines tested. Since (S)-lacosamide is bioavailable in the brain, we tested its utility in an in vivo orthotopic model of GBM using GL261-LucNeo glioma cells. (S)-lacosamide decreased tumor size, as measured via in vivo bioluminescence imaging, by ~54% compared to vehicle control. Our results introduce CRMP2 expression and phosphorylation as a novel player in GBM proliferation and survival, which is enhanced by loss of Nf1.

• Authors: Aubin Moutal, Lex Salas Villa, Seul Ki Yeon, Kyle T Householder, Ki Duk Park, Rachael W Sirianni, Rajesh Khanna
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 55 Issue 5 Pg. 4403-4416 (May 2018) ISSN: 1559-1182 [Electronic] United States
• PMID: 28660485 (Publication Type: Journal Article)

Chemical References

• Intercellular Signaling Peptides and Proteins
• Nerve Tissue Proteins
• Neurofibromin 1
• collapsin response mediator protein-2
• Lacosamide

Topics

• Animals
• Apoptosis (drug effects)
• Brain Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Cell Nucleus (metabolism, pathology)
• Cell Proliferation (drug effects)
• Glioblastoma (metabolism, pathology)
• Humans
• Intercellular Signaling Peptides and Proteins (metabolism)
• Lacosamide (pharmacology)
• Mice, Inbred C57BL
• Nerve Tissue Proteins (metabolism)
• Neurofibromin 1 (metabolism)
• Phosphorylation (drug effects)