Glioma-derived cancer stem cells are hypersensitive to proteasomal inhibition

Young Dong Yoo, Dae Hee Lee, Hyunjoo Cha-Molstad, Hyungsin Kim, Su Ran Mun, Changhoon Ji, Seong Hye Park, Ki Sa Sung, Seung Ah Choi, Joonsung Hwang, Deric M. Park, Seung Ki Kim, Kyung-Jae Park, Shin-Hyuk Kang, Sang Cheul Oh, Aaron Ciechanover, Yong J. Lee, Bo Yeon Kim, Yong Tae Kwon

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5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)150-168
Number of pages19
JournalEMBO Reports
Volume18
Issue number1
DOIs
Publication statusPublished - 2017 Jan 1

Keywords

  • apoptosis
  • c-Jun N-terminal kinase
  • glioma stem cells
  • proteasome inhibitors
  • ubiquitin proteasome system

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Yoo, Y. D., Lee, D. H., Cha-Molstad, H., Kim, H., Mun, S. R., Ji, C., Park, S. H., Sung, K. S., Choi, S. A., Hwang, J., Park, D. M., Kim, S. K., Park, K-J., Kang, S-H., Oh, S. C., Ciechanover, A., Lee, Y. J., Kim, B. Y., & Kwon, Y. T. (2017). Glioma-derived cancer stem cells are hypersensitive to proteasomal inhibition. EMBO Reports, 18(1), 150-168. https://doi.org/10.15252/embr.201642360