The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5

• Type of Material: Article
• Authors: Youtake Oh, Emory University; Liang Deng, Emory Univeristy; Jiusheng Deng, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2017-08-14
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-017-08424-w
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 7
• Issue: 1
• Start Page: 8027
• End Page: 8027
• Grant/Funding Information: This study was supported by Emory Winship Cancer Institute Halpern Research Scholar award. S.-Y. Sun is an Emory Winship Cancer Institute Halpern Research Scholar and a Georgia Research Alliance Distinguished Cancer Scientist.
• Keywords: MULTIPLE-MYELOMA; DOWN-REGULATION CONTRIBUTES; TRAIL-INDUCED APOPTOSIS; C-FLIP DEGRADATION; MEDIATED APOPTOSIS; Science & Technology; UP-REGULATION; Multidisciplinary Sciences; TUMOR-CELLS; DEATH RECEPTOR 5; NATURAL-KILLER-CELLS; Science & Technology - Other Topics; LUNG-CANCER CELLS
• Research Categories: Health Sciences, Oncology

Abstract

b-AP15 and its derivatives block proteasome deubiquitinase (DUB) activity and have been developed and tested in the clinic as potential cancer therapeutic agents. b-AP15 induces apoptosis in cancer cells, but the underlying mechanisms are largely undefined. The current study focuses on studying the modulatory effects of b-AP15 on death receptor 5 (DR5) levels and DR5 activation-induced apoptosis as well as on understanding the underlying mechanisms. Treatment with b-AP15 potently increased DR5 levels including cell surface DR5 in different cancer cell lines with limited or no effects on the levels of other related proteins including DR4, c-FLIP, FADD, and caspase-8. b-AP15 substantially slowed the degradation of DR5, suggesting that it stabilizes DR5. Moreover, b-AP15 effectively augmented apoptosis when combined with TRAIL or the DR5 agonistic antibody AMG655; these effects are DR5-dependent because DR5 deficiency abolished the ability of b-AP15 to enhance TRAIL-or AMG655-induced apoptosis. Therefore, it is clear that b-AP15, and possibly its derivatives, can stabilize DR5 and increase functional cell surface DR5 levels, resulting in enhancement of DR5 activation-induced apoptosis. Our findings suggest that b-AP15 and its derivatives may have potential in sensitizing cancer cells to DR5 activation-based cancer therapy.