机构：[1]Department of Hematology and Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA[2]State Key Laboratory of Oral Disease and Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China[3]Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute and School of Medicine, Pittsburgh, PA, USA[4]Beijing Institute of Basic Medical Sciences, Beijing, PR China
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.
基金：
This study was supported by Emory Winship Cancer Institute Halpern Research Scholar award (to SYS) and Melanoma Research Fund (to JD).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2015]版：
大类|1 区医学
小类|2 区肿瘤学3 区细胞生物学
最新[2023]版：
无
第一作者：
第一作者机构：[1]Department of Hematology and Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA[2]State Key Laboratory of Oral Disease and Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
通讯作者：
推荐引用方式(GB/T 7714)：
Bo Han,Weilong Yao,You-Take Oh,et al.The novel proteasome inhibitor carfilzomib activates and enhances extrinsic apoptosis involving stabilization of death receptor 5.[J].Oncotarget.2015,6(19):17532-42.doi:10.18632/oncotarget.3947.
APA：
Bo Han,Weilong Yao,You-Take Oh,Jing-Shan Tong,Shaohua Li...&Shi-Yong Sun.(2015).The novel proteasome inhibitor carfilzomib activates and enhances extrinsic apoptosis involving stabilization of death receptor 5..Oncotarget,6,(19)
MLA：
Bo Han,et al."The novel proteasome inhibitor carfilzomib activates and enhances extrinsic apoptosis involving stabilization of death receptor 5.".Oncotarget 6..19(2015):17532-42
医学