@article{31f89dbf89954830887b87018ce60539,
title = "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.",
keywords = "(S)-lacosamide, CRMP2, Glioblastoma, Neurofibromin, Phosphorylation, Proliferation",
author = "Aubin Moutal and Villa, {Lex Salas} and Yeon, {Seul Ki} and Householder, {Kyle T.} and Park, {Ki Duk} and Sirianni, {Rachael W.} and Rajesh Khanna",
note = "Funding Information: Acknowledgements This work was supported by a Neurofibromatosis New Investigator Award from the Department of Defense Congressionally Directed Military Medical Research and Development Program (NF1000099) and a Children{\textquoteright}s Tumor Foundation NF1 Synodos award to R.K. A.M. was supported by a Young Investigator{\textquoteright}s Award from the Children{\textquoteright}s Tumor Foundation. L.S.V. was supported by grants from a T35 HL07479-31A1 training grant from the NIH/NHLBI to Marlys H. Witte (Department of Surgery, University of Arizona) as well as a grant from the Undergraduate Biology Research Program (UBRP), University of Arizona and Western Alliance to Expand Student Opportunities (WAESO) Louis Stokes Alliance for Minority Participation (LSAMP) National Science Foundation (NSF) Cooperative Agreement No. HRD-1101728. Further support was provided by Arizona State University (K.T.H.) and the Barrow Neurological Foundation (K.T.H., R.W.S.) Funding Information: This work was supported by a Neurofibromatosis New Investigator Award from the Department of Defense Congressionally Directed Military Medical Research and Development Program (NF1000099) and a Children?s Tumor Foundation NF1 Synodos award to R.K. A.M. was supported by a Young Investigator?s Award from the Children?s Tumor Foundation. L.S.V. was supported by grants from a T35 HL07479-31A1 training grant from the NIH/NHLBI to Marlys H. Witte (Department of Surgery, University of Arizona) as well as a grant from the Undergraduate Biology Research Program (UBRP), University of Arizona and Western Alliance to Expand Student Opportunities (WAESO) Louis Stokes Alliance for Minority Participation (LSAMP) National Science Foundation (NSF) Cooperative Agreement No. HRD-1101728. Further support was provided by Arizona State University (K.T.H.) and the Barrow Neurological Foundation (K.T.H., R.W.S.) The authors declare that they have no conflict of interest. Publisher Copyright: {\textcopyright} 2017, Springer Science+Business Media, LLC.",
year = "2018",
month = may,
day = "1",
doi = "10.1007/s12035-017-0653-9",
language = "English (US)",
volume = "55",
pages = "4403--4416",
journal = "Molecular Neurobiology",
issn = "0893-7648",
publisher = "Humana Press",
number = "5",
}