Bortezomib sensitizes human glioblastoma cells to induction of apoptosis by type I interferons through NOXA expression and Mcl-1 cleavage

Ruishan Wang; Andrew M Davidoff; Lawrence M Pfeffer

doi:10.1016/j.bbrc.2016.07.080

Bortezomib sensitizes human glioblastoma cells to induction of apoptosis by type I interferons through NOXA expression and Mcl-1 cleavage

Biochem Biophys Res Commun. 2016 Sep 9;478(1):128-134. doi: 10.1016/j.bbrc.2016.07.080. Epub 2016 Jul 20.

Authors

Ruishan Wang¹, Andrew M Davidoff², Lawrence M Pfeffer³

Affiliations

¹ 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.
² Department of Pathology and Laboratory Medicine, Memphis, TN, USA; Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA.
³ Department of Pathology and Laboratory Medicine, Memphis, TN, USA; Center for Cancer Research, Memphis, TN, USA. Electronic address: [email protected].

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.

Keywords: Apoptosis; Bortezomib; Glioblastoma; Interferon.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antineoplastic Agents / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / administration & dosage
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Apoptosis / drug effects
Bortezomib / administration & dosage
Bortezomib / pharmacology*
Brain / drug effects
Brain / metabolism
Brain Neoplasms / drug therapy*
Brain Neoplasms / genetics
Brain Neoplasms / metabolism
Cell Line, Tumor
Glioblastoma / drug therapy*
Glioblastoma / genetics
Glioblastoma / metabolism
Humans
Interferon Type I / administration & dosage
Interferon Type I / pharmacology*
Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
Proteolysis / drug effects
Proto-Oncogene Proteins c-bcl-2 / genetics*
Up-Regulation / drug effects

Substances

Antineoplastic Agents
Interferon Type I
MCL1 protein, human
Myeloid Cell Leukemia Sequence 1 Protein
PMAIP1 protein, human
Proto-Oncogene Proteins c-bcl-2
Bortezomib

Grants and funding

R01 CA133322/CA/NCI NIH HHS/United States