PUBLICATION

PRMT5 as a druggable target for glioblastoma therapy

Authors
Banasavadi-Siddegowda, Y.K., Welker, A.M., An, M., Yang, X., Zhou, W., Shi, G., Imitola, J., Li, C., Hsu, S., Wang, J., Phelps, M., Zhang, J., Beattie, C.E., Baiocchi, R., Kaur, B.
ID
ZDB-PUB-171107-9
Date
2017
Source
Neuro-Oncology   20(6): 753-763 (Journal)
Registered Authors
An, Min, Beattie, Christine
Keywords
CMP5, GBM, PRMT5, glioma, senescence
MeSH Terms
  • Animals
  • Apoptosis
  • Brain Neoplasms/drug therapy
  • Brain Neoplasms/metabolism
  • Brain Neoplasms/pathology*
  • Cell Cycle
  • Cell Differentiation
  • Cell Proliferation
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic/drug effects*
  • Glioblastoma/drug therapy
  • Glioblastoma/metabolism
  • Glioblastoma/pathology*
  • Humans
  • Mice
  • Protein Kinase Inhibitors/pharmacology*
  • Protein-Arginine N-Methyltransferases/antagonists & inhibitors*
  • Protein-Arginine N-Methyltransferases/genetics
  • Protein-Arginine N-Methyltransferases/metabolism
  • Signal Transduction
  • Small Molecule Libraries/pharmacology*
  • Spheroids, Cellular
  • Xenograft Model Antitumor Assays
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Zebrafish/metabolism*
PubMed
29106602 Full text @ Neuro Oncol.
Abstract
In spite of standard multi modal therapy consisting of surgical resection followed by radiation and concurrent chemotherapy prognosis for GBM patients remains poor. The identification of both differentiated and undifferentiated "stem cell like" populations in the tumor highlights the significance of finding novel targets that affect the heterogenous tumor cell population. Protein arginine methyltransferase (PRMT5) is one such candidate gene whose nuclear expression correlates with poor survival and has been reported to be required for survival of differentiated GBM cells and self-renewal of undifferentiated GBM cells. In the current study we screened the specificity and efficacy of four novel PRMT5 inhibitors in the treatment of GBM.
Efficacies of these inhibitors were screened using in vitro GBM neurosphere model and in vivo intracranial zebrafish model of glioma. Standard molecular biology methods were employed to investigate changes in cell cycle, growth, and senescence.
In vitro and In vivo studies revealed that among the four PRMT5 inhibitors, treatment of GBM cells with compound 5 (CMP5) mirrored the effects of PRMT5 knock down wherein it led to apoptosis of differentiated GBM cells, and drove undifferentiated primary patient derived GBM cells into a non replicative senescent state.
In vivo antitumor efficacy combined with the specificity of CMP5 underscores the importance of developing it for translation.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes