Glioma-derived cancer stem cells are hypersensitive to proteasomal inhibition

EMBO Rep. 2017 Jan;18(1):150-168. doi: 10.15252/embr.201642360. Epub 2016 Dec 19.

Abstract

Although proteasome inhibitors (PIs) are used as anticancer drugs to treat various cancers, their relative therapeutic efficacy on stem cells vs. bulk cancers remains unknown. Here, we show that stem cells derived from gliomas, GSCs, are up to 1,000-fold more sensitive to PIs (IC50, 27-70 nM) compared with their differentiated controls (IC50, 47 to »100 μM). The stemness of GSCs correlates to increased ubiquitination, whose misregulation readily triggers apoptosis. PI-induced apoptosis of GSCs is independent of NF-κB but involves the phosphorylation of c-Jun N-terminal kinase as well as the transcriptional activation of endoplasmic reticulum (ER) stress-associated proapoptotic mediators. In contrast to the general notion that ER stress-associated apoptosis is signaled by prolonged unfolded protein response (UPR), GSC-selective apoptosis is instead counteracted by the UPR ATF3 is a key mediator in GSC-selective apoptosis. Pharmaceutical uncoupling of the UPR from its downstream apoptosis sensitizes GSCs to PIs in vitro and during tumorigenesis in mice. Thus, a combinational treatment of a PI with an inhibitor of UPR-coupled apoptosis may enhance targeting of stem cells in gliomas.

Keywords: apoptosis; c‐Jun N‐terminal kinase; glioma stem cells; proteasome inhibitors; ubiquitin proteasome system.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Biomarkers
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioma / drug therapy
  • Glioma / genetics
  • Glioma / metabolism*
  • Glioma / pathology
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Models, Biological
  • NF-kappa B / metabolism
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism*
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / pharmacology*
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured
  • Ubiquitination / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Biomarkers
  • NF-kappa B
  • Proteasome Inhibitors
  • JNK Mitogen-Activated Protein Kinases
  • Proteasome Endopeptidase Complex