title: The novel proteasome inhibitor carfilzomib activates and enhances extrinsic apoptosis involving stabilization of death receptor 5.
abstract: Carfilzomib (CFZ) is a second generation proteasome inhibitor approved for the treatment of patients with multiple myeloma. It induces apoptosis in human cancer cells; but the underlying mechanisms remain undefined. In the present study, we show that CFZ decreases the survival of several human cancer cell lines and induces apoptosis. Induction of apoptosis by CFZ occurs, at least in part, due to activation of the extrinsic apoptotic pathway, since FADD deficiency protected cancer cells from undergoing apoptosis. CFZ increased total and cell surface levels of DR5 in different cancer cell lines; accordingly it enhanced TRAIL-induced apoptosis. DR5 deficiency protected cancer cells from induction of apoptosis by CFZ either alone or in combination with TRAIL. These data together convincingly demonstrate that DR5 upregulation is a critical mechanism accounting for CFZ-induced apoptosis and enhancement of TRAIL-induced apoptosis. CFZ inhibited the degradation of DR5, suggesting that DR5 stabilization contributes to CFZ-induced DR5 upregulation. In summary, the present study highlights the important role of DR5 upregulation in CFZ-induced apoptosis and enhancement of TRAIL-induced apoptosis in human cancer cells.
authors.affiliation: Department of Hematology and Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.|State Key Laboratory of Oral Disease and Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of Hematology and Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: Weilong
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Hematology and Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: You-Take
authors.initials: YT
authors.lastname: Oh
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute and School of Medicine, Pittsburgh, PA, USA.
authors.forename: Jing-Shan
authors.initials: JS
authors.lastname: Tong
authors.affiliation: Department of Hematology and Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.|Beijing Institute of Basic Medical Sciences, Beijing, PR China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Hematology and Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: Jiusheng
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Hematology and Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Yue
authors.affiliation: Department of Hematology and Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Department of Hematology and Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C524865:carfilzomib
keywords: carfilzomib; death receptor 5; extrinsic apoptosis; proteasome inhibitors