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

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 stud...

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Autores principales:	You-Take Oh, Liang Deng, Jiusheng Deng, Shi-Yong Sun
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/38f8016a0030447e8e7e8736ee71973b
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spelling	oai:doaj.org-article:38f8016a0030447e8e7e8736ee71973b2021-12-02T12:32:43ZThe proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR510.1038/s41598-017-08424-w2045-2322https://doaj.org/article/38f8016a0030447e8e7e8736ee71973b2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08424-whttps://doaj.org/toc/2045-2322Abstract 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.You-Take OhLiang DengJiusheng DengShi-Yong SunNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q You-Take Oh Liang Deng Jiusheng Deng Shi-Yong Sun The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5
description	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.
format	article
author	You-Take Oh Liang Deng Jiusheng Deng Shi-Yong Sun
author_facet	You-Take Oh Liang Deng Jiusheng Deng Shi-Yong Sun
author_sort	You-Take Oh
title	The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5
title_short	The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5
title_full	The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5
title_fullStr	The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5
title_full_unstemmed	The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5
title_sort	proteasome deubiquitinase inhibitor b-ap15 enhances dr5 activation-induced apoptosis through stabilizing dr5
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/38f8016a0030447e8e7e8736ee71973b
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The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5

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