title: Bortezomib sensitizes human glioblastoma cells to induction of apoptosis by type I interferons through NOXA expression and Mcl-1 cleavage.
abstract: Glioblastomas are highly invasive and aggressive primary brain tumors. Type I interferons have significant, pleiotropic anticancer activity. However, through various pathways many cancers become interferon-resistant, limiting interferon's clinical utility. In this study, we demonstrated that the proteasomal inhibitor bortezomib sensitized human glioblastoma cells to the antiproliferative action of interferons, which involved the induction of caspase-dependent apoptosis but not necroptosis. We found that death ligands such as TRAIL (TNF-related apoptosis-inducing ligand) were not involved in interferon/bortezomib-induced apoptosis, although interferon induced TRAIL expression. However, apoptosis was induced through an intrinsic pathway involving increased NOXA expression and Mcl-1 cleavage. Our findings may provide an important rationale for combining type I interferons with bortezomib for glioblastoma therapy.
authors.affiliation: Department of Pathology and Laboratory Medicine, Memphis, TN, USA; Center for Cancer Research, Memphis, TN, USA; Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Ruishan
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, Memphis, TN, USA; Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
authors.affiliation: Department of Pathology and Laboratory Medicine, Memphis, TN, USA; Center for Cancer Research, Memphis, TN, USA. Electronic address: lpfeffer@uthsc.edu.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000008:administration & dosage / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007370:Interferon Type I; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D000069286:Bortezomib
keywords: Apoptosis; Bortezomib; Glioblastoma; Interferon