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. (C) 2016 Elsevier Inc. All rights reserved.