title: Bortezomib stabilizes NOXA and triggers ROS-associated apoptosis in medulloblastoma.
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.
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ohshima-Hosoyama
authors.forename: Monika A
authors.initials: MA
authors.lastname: Davare
authors.forename: Tohru
authors.initials: T
authors.lastname: Hosoyama
authors.forename: Laura D
authors.initials: LD
authors.lastname: Nelon
authors.forename: Charles
authors.initials: C
authors.lastname: Keller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002478:Cells, Cultured; D002528:Cerebellar Neoplasms / Q000378:metabolism*; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D008527:Medulloblastoma / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000069286:Bortezomib