Document Type
Article
Department/Program
Natural Science & Mathematics
Journal Title
Clinical Cancer Research
Pub Date
6-1-2012
Volume
18
Issue
11
Journal Article URL
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756473/
First Page
3030
Abstract
Purpose
This study assessed whether Myristoylated Alanine Rich C-Kinase Substrate (MARCKS) can regulate glioblastoma (GBM) growth, radiation sensitivity and clinical outcome.
Experimental Design
MARCKS protein levels were analyzed in five GBM explant cell lines and eight patient-derived xenograft tumors by immunoblot, and these levels were correlated to proliferation rates and intracranial growth rates, respectively. Manipulation of MARCKS protein levels was assessed by lentiviral-mediated shRNA knockdown in the U251 cell line and MARCKS over-expression in the U87 cell line. The effect of manipulation of MARCKS on proliferation, radiation sensitivity and senescence was assessed. MARCKS gene expression was correlated with survival outcomes in the Repository of Molecular Brain Neoplasia Data (REMBRANDT) Database and The Cancer Genome Atlas (TCGA).
Results
MARCKS protein expression was inversely correlated with GBM proliferation and intracranial xenograft growth rates. Genetic silencing of MARCKS promoted GBM proliferation and radiation resistance, while MARCKS overexpression greatly reduced GBM growth potential and induced senescence. We found MARCKS gene expression to be directly correlated with survival in both the REMBRANDT and TCGA databases. Specifically, patients with high MARCKS expressing tumors of the Proneural molecular subtype had significantly increased survival rates. This effect was most pronounced in tumors with unmethylated O6-methylguanine DNA methyltransferase (MGMT) promoters, a traditionally poor prognostic factor.
Conclusions
MARCKS levels impact GBM growth and radiation sensitivity. High MARCKS expressing GBM tumors are associated with improved survival, particularly with unmethylated MGMT promoters. These findings suggest the use of MARCKS as a novel target and biomarker for prognosis in the Proneural subtype of GBM.
Recommended Citation
Jarboe, J. S., Anderson, J. C., Duarte, C. W., Mehta, T., Nowsheen, S., Hicks, P. H., Whitley, A. C., Rohrbach, T. D., McCubrey, R. O., Chiu, S., Burleson, T. M., Bonner, J. A., Gillespie, G. Y., Yang, E. S., & Willey, C. D. (2012). MARCKS regulates growth and radiation sensitivity and is a novel prognostic factor for glioma. Clinical cancer research : an official journal of the American Association for Cancer Research, 18(11), 3030–3041. https://doi.org/10.1158/1078-0432.CCR-11-3091
DOI
https://doi.org/10.1158/1078-0432.CCR-11-3091
Publisher Statement
Clin Cancer Res. Author manuscript; available in PMC 2013 Aug 29. Published in final edited form as: Clin Cancer Res. 2012 Jun 1; 18(11): 3030–3041. Published online 2012 May 22. doi: 10.1158/1078-0432.CCR-11-3091
