Research Papers:

The novel proteasome inhibitor carfilzomib activates and enhances extrinsic apoptosis involving stabilization of death receptor 5

Bo Han _, Weilong Yao, You-Take Oh, Jing-Shan Tong, Shaohua Li, Jiusheng Deng, Ping Yue, Fadlo R. Khuri and Shi-Yong Sun

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Oncotarget. 2015; 6:17532-17542. https://doi.org/10.18632/oncotarget.3947

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Bo Han1,2, Weilong Yao1, You-Take Oh1, Jing-Shan Tong3, Shaohua Li1,4, Jiusheng Deng1, Ping Yue1, Fadlo R. Khuri1, Shi-Yong Sun1

1Department of Hematology and Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA

2State Key Laboratory of Oral Disease and Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China

3Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute and School of Medicine, Pittsburgh, PA, USA

4Beijing Institute of Basic Medical Sciences, Beijing, PR China

Correspondence to:

Shi-Yong Sun, e-mail: [email protected]

Keywords: proteasome inhibitors, carfilzomib, death receptor 5, extrinsic apoptosis

Received: March 13, 2015     Accepted: April 28, 2015     Published: May 11, 2015


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.

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