title: MARCKS regulates growth and radiation sensitivity and is a novel prognostic factor for glioma.
abstract: OBJECTIVE
  This study assessed whether myristoylated alanine-rich C-kinase substrate (MARCKS) can regulate glioblastoma multiforme (GBM) growth, radiation sensitivity, and clinical outcome.
  
  
  METHODS
  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 short hairpin RNA knockdown in the U251 cell line and MARCKS 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 of MARCKS promoted GBM proliferation and radiation resistance, whereas 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 O(6)-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.
authors.affiliation: The Departments of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL 35249, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Jarboe
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Anderson
authors.forename: Christine W
authors.initials: CW
authors.lastname: Duarte
authors.forename: Tapan
authors.initials: T
authors.lastname: Mehta
authors.forename: Somaira
authors.initials: S
authors.lastname: Nowsheen
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Hicks
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Whitley
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Rohrbach
authors.forename: Raymond O
authors.initials: RO
authors.lastname: McCubrey
authors.forename: Sherard
authors.initials: S
authors.lastname: Chiu
authors.forename: Tamara M
authors.initials: TM
authors.lastname: Burleson
authors.forename: James A
authors.initials: JA
authors.lastname: Bonner
authors.forename: G Yancey
authors.initials: GY
authors.lastname: Gillespie
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Yang
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Willey
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009368:Neoplasm Transplantation; D011379:Prognosis; D011836:Radiation Tolerance; D014183:Transplantation, Heterologous
chemical_list: D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate