Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis

Nat Commun. 2014 Aug 18;5:4632. doi: 10.1038/ncomms5632.

Abstract

Gliomas are the most common primary tumours affecting the adult central nervous system and respond poorly to standard therapy. Myc is causally implicated in most human tumours and the majority of glioblastomas have elevated Myc levels. Using the Myc dominant negative Omomyc, we previously showed that Myc inhibition is a promising strategy for cancer therapy. Here, we preclinically validate Myc inhibition as a therapeutic strategy in mouse and human glioma, using a mouse model of spontaneous multifocal invasive astrocytoma and its derived neuroprogenitors, human glioblastoma cell lines, and patient-derived tumours both in vitro and in orthotopic xenografts. Across all these experimental models we find that Myc inhibition reduces proliferation, increases apoptosis and remarkably, elicits the formation of multinucleated cells that then arrest or die by mitotic catastrophe, revealing a new role for Myc in the proficient division of glioma cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Astrocytoma / pathology*
  • Astrocytoma / physiopathology
  • Astrocytoma / therapy
  • Brain Neoplasms / pathology*
  • Brain Neoplasms / physiopathology
  • Brain Neoplasms / therapy
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Disease Models, Animal
  • Glioblastoma / pathology*
  • Glioblastoma / physiopathology
  • Glioblastoma / therapy
  • Glioma / pathology*
  • Glioma / physiopathology
  • Glioma / therapy
  • Heterografts
  • Humans
  • Mice
  • Mice, Transgenic
  • Mitosis / physiology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / physiology
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / physiology
  • Ubiquitin-Activating Enzymes / physiology

Substances

  • MYC protein, human
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • SAE1 protein, mouse
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Ptpn1 protein, mouse
  • SAE1 protein, human
  • Ubiquitin-Activating Enzymes