Bortezomib stabilizes NOXA and triggers ROS-associated apoptosis in medulloblastoma

Sachiko Ohshima-Hosoyama, Monika Davare, Tohru Hosoyama, Laura D. Nelon, Charles Keller

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

We have previously demonstrated that bortezomib, a 26S proteasome inhibitor, effectively inhibits medulloblastoma growth in vivo in a genetically engineered Ptch1, p53 mouse model; however, bortezomib is also associated clinically with severe peripheral neuropathy, which would be disadvantageous for patients with central nervous system malignancy. The purpose of this study was to determine the mechanism of bortezomib efficacy in medulloblastoma in order to replicate more specifically the therapeutic advantage of targeting the ubiquitin-proteosome system. In our studies of upstream components of the ubiquitin-proteasome system, we identified the pro-apoptotic protein NOXA as a post-translationally modified target that is stabilized by bortezomib and induces caspase cleavage in the context of reactive oxidative stress induced cell death. These preclinical results may apply to the sizable fraction of Shh-driven human medulloblastoma and perhaps other medulloblastoma subtypes, independent of p53 status.

Original languageEnglish (US)
Pages (from-to)475-483
Number of pages9
JournalJournal of Neuro-Oncology
Volume105
Issue number3
DOIs
Publication statusPublished - Dec 2011

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Keywords

  • Bortezomib
  • E3 ubiquitin ligase
  • Medulloblastoma
  • NOXA
  • Ptch1
  • ROS

ASJC Scopus subject areas

  • Clinical Neurology
  • Cancer Research
  • Oncology
  • Neurology

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