Human Cancer Biology MARCKS Regulates Growth and Radiation Sensitivity and Is a Novel Prognostic Factor for Glioma

Purpose: This study assessed whether myristoylated alanine-rich C-kinase substrate (MARCKS) can regulate glioblastoma multiforme (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 lentiviralmediated short hairpin RNA knockdown in the U251 cell line andMARCKS overexpression 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 ofMARCKS promotedGBMproliferation and radiation resistance, whereasMARCKSoverexpression greatly reducedGBMgrowth 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 effectwasmost pronounced in tumorswithunmethylatedOmethylguanine 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. Clin Cancer Res; 18(11); 3030–41. 2012 AACR.