N-CoR pathway targeting induces glioblastoma derived cancer stem cell differentiation.
Nuclear receptor corepressor (N-CoR) is a critical regulator of neural stem cell differentiation. Nuclear localization of N-CoR is a feature of undifferentiated neural stem cells and cytoplasmic translocation of N-CoR leads to astrocytic differentiation. Comparative proteomic analysis of microdissected glioblastoma multiforme (GBM) specimens and matched normal glial tissue reveals increased expression of N-CoR in GBM. In GBM primary cell cultures, tumor cells with nuclear localization of N-CoR demonstrate an undifferentiated phenotype, but are subject to astroglial differentiation upon exposure to agents promoting phosphorylation of N-CoR and its subsequent translocation to the cytoplasm. Treatment of glioma cell lines with a combination of retinoic acid and low-dose okadaic acid decreases the corepressor effect of N-CoR and has a striking synergistic effect on growth inhibition. The identification of N-CoR in GBM provides insights into the tumorigenesis process and supports the development of differentiation-based therapeutic strategies.
Park
Deric M
DM
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Li
Jie
J
Okamoto
Hiroaki
H
Akeju
Oluwaseun
O
Kim
Stephanie H
SH
Lubensky
Irina
I
Vortmeyer
Alexander
A
Dambrosia
James
J
Weil
Robert J
RJ
Oldfield
Edward H
EH
Park
John K
JK
Zhuang
Zhengping
Z
D015415:Biomarkers / Q000032:analysis; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D056971:Nuclear Receptor Co-Repressor 1; D019319:Okadaic Acid / Q000008:administration & dosage / Q000494:pharmacology; D010766:Phosphorylation; D021381:Protein Transport; D012097:Repressor Proteins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D015415:Biomarkers; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D012097:Repressor Proteins; D019319:Okadaic Acid; D014212:Tretinoin