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Tumor necrosis factor related apoptosis inducing ligand (TRAIL) regulates deubiquitinase USP5 in tumor cells

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway has emerged as a cancer therapeutic target. However, clinical trials have proven that most human cancers are resistant to TRAIL. We show that exposure to recombinant TRAIL resulted in the accumulation of ubiquitinated protei...

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Autores principales: Potu, Harish, Kandarpa, Malathi, Peterson, Luke F., Donato, Nicholas J., Talpaz, Moshe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791380/
https://www.ncbi.nlm.nih.gov/pubmed/31645897
http://dx.doi.org/10.18632/oncotarget.27196
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author Potu, Harish
Kandarpa, Malathi
Peterson, Luke F.
Donato, Nicholas J.
Talpaz, Moshe
author_facet Potu, Harish
Kandarpa, Malathi
Peterson, Luke F.
Donato, Nicholas J.
Talpaz, Moshe
author_sort Potu, Harish
collection PubMed
description The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway has emerged as a cancer therapeutic target. However, clinical trials have proven that most human cancers are resistant to TRAIL. We show that exposure to recombinant TRAIL resulted in the accumulation of ubiquitinated proteins and free ubiquitin polymers, suggesting a link between TRAIL and the ubiquitin (Ub)-proteasome pathway. TRAIL treatment in cancer cells reduced the activity and cleavage of USP5, a deubiquitinase (DUB) previously shown to target unanchored Ub polymers and regulate p53-mediated transcription. TRAIL was effective in suppressing USP5 activity and cleavage in TRAIL-sensitive cells but not resistant cells. Knockdown of USP5 in TRAIL-resistant cells demonstrated that USP5 controls apoptotic responsiveness to TRAIL. USP5 cleavage and ubiquitination were blocked by caspase-8 specific inhibitors. A small-molecule USP5/9× inhibitor (G9) combined with TRAIL enhanced apoptosis and blocked colony growth in highly TRAIL-resistant cell lines. Finally, USP5 protein levels and activity were found to be frequently deregulated in TRAIL-resistant cells. Together, we conclude that activated TRAIL enhances USP5 activity and induces apoptosis in TRAIL-sensitive and -resistant cells. We also suggest that USP5 inhibition may be effective in inducing apoptotic thresholds to enhance responsiveness to TRAIL.
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spelling pubmed-67913802019-10-23 Tumor necrosis factor related apoptosis inducing ligand (TRAIL) regulates deubiquitinase USP5 in tumor cells Potu, Harish Kandarpa, Malathi Peterson, Luke F. Donato, Nicholas J. Talpaz, Moshe Oncotarget Research Paper The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway has emerged as a cancer therapeutic target. However, clinical trials have proven that most human cancers are resistant to TRAIL. We show that exposure to recombinant TRAIL resulted in the accumulation of ubiquitinated proteins and free ubiquitin polymers, suggesting a link between TRAIL and the ubiquitin (Ub)-proteasome pathway. TRAIL treatment in cancer cells reduced the activity and cleavage of USP5, a deubiquitinase (DUB) previously shown to target unanchored Ub polymers and regulate p53-mediated transcription. TRAIL was effective in suppressing USP5 activity and cleavage in TRAIL-sensitive cells but not resistant cells. Knockdown of USP5 in TRAIL-resistant cells demonstrated that USP5 controls apoptotic responsiveness to TRAIL. USP5 cleavage and ubiquitination were blocked by caspase-8 specific inhibitors. A small-molecule USP5/9× inhibitor (G9) combined with TRAIL enhanced apoptosis and blocked colony growth in highly TRAIL-resistant cell lines. Finally, USP5 protein levels and activity were found to be frequently deregulated in TRAIL-resistant cells. Together, we conclude that activated TRAIL enhances USP5 activity and induces apoptosis in TRAIL-sensitive and -resistant cells. We also suggest that USP5 inhibition may be effective in inducing apoptotic thresholds to enhance responsiveness to TRAIL. Impact Journals LLC 2019-10-08 /pmc/articles/PMC6791380/ /pubmed/31645897 http://dx.doi.org/10.18632/oncotarget.27196 Text en Copyright: © 2019 Potu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Potu, Harish
Kandarpa, Malathi
Peterson, Luke F.
Donato, Nicholas J.
Talpaz, Moshe
Tumor necrosis factor related apoptosis inducing ligand (TRAIL) regulates deubiquitinase USP5 in tumor cells
title Tumor necrosis factor related apoptosis inducing ligand (TRAIL) regulates deubiquitinase USP5 in tumor cells
title_full Tumor necrosis factor related apoptosis inducing ligand (TRAIL) regulates deubiquitinase USP5 in tumor cells
title_fullStr Tumor necrosis factor related apoptosis inducing ligand (TRAIL) regulates deubiquitinase USP5 in tumor cells
title_full_unstemmed Tumor necrosis factor related apoptosis inducing ligand (TRAIL) regulates deubiquitinase USP5 in tumor cells
title_short Tumor necrosis factor related apoptosis inducing ligand (TRAIL) regulates deubiquitinase USP5 in tumor cells
title_sort tumor necrosis factor related apoptosis inducing ligand (trail) regulates deubiquitinase usp5 in tumor cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791380/
https://www.ncbi.nlm.nih.gov/pubmed/31645897
http://dx.doi.org/10.18632/oncotarget.27196
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