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.
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Acknowledgments
This work was supported by research grantsBrain Tumor from the National Brain Tumor Society and the Hyundai Motor Corporation Hope on Wheels Program. We thank Dr. Owen Lockerbie, Peter G. Smith and their colleagues at Millennium Pharmaceuticals for kindly providing MLN-4924. We are grateful to Drs. Richard Gilbertson and Martine Roussel for advice and guidance in the culture of primary medulloblastoma tumor cells.
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Sachiko Ohshima-Hosoyama and Monika A. Davare contributed equally to this work.
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Ohshima-Hosoyama, S., Davare, M.A., Hosoyama, T. et al. Bortezomib stabilizes NOXA and triggers ROS-associated apoptosis in medulloblastoma. J Neurooncol 105, 475–483 (2011). https://doi.org/10.1007/s11060-011-0619-0
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DOI: https://doi.org/10.1007/s11060-011-0619-0