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BRD4 inhibition promotes TRAIL-induced apoptosis by suppressing the transcriptional activity of NF-κB in NSCLC

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and agonistic antibodies against TRAIL death receptors (DR) can induce apoptosis preferentially in tumor cells while causing virtually no damage to normal cells. However, their therapeutic potential is limited by occurring resistance in...

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Autores principales: Shi, Liu, Xiong, Yu, Hu, Xiaoyan, Wang, Zhihao, Xie, Conghua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364464/
https://www.ncbi.nlm.nih.gov/pubmed/34400879
http://dx.doi.org/10.7150/ijms.60776
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author Shi, Liu
Xiong, Yu
Hu, Xiaoyan
Wang, Zhihao
Xie, Conghua
author_facet Shi, Liu
Xiong, Yu
Hu, Xiaoyan
Wang, Zhihao
Xie, Conghua
author_sort Shi, Liu
collection PubMed
description Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and agonistic antibodies against TRAIL death receptors (DR) can induce apoptosis preferentially in tumor cells while causing virtually no damage to normal cells. However, their therapeutic potential is limited by occurring resistance in tumor cells, including non-small cell lung cancer (NSCLC). Thus, elucidation of the molecular targets and signaling pathways responsible for TRAIL resistance is imperative for devising effective therapeutic strategies for TRAIL resistant cancers. In the present study, we demonstrated that inhibition of Bromodomain-containing protein 4 (BRD4) or genetic knock-down of BRD4, an epigenetic reader and master transcription coactivator, can sensitize lung cancer cells to TRAIL. This sensitization is in a caspase-dependent manner. Inhibition of BRD4 by small molecule inhibitor (+)-JQ-1 and genetic knock-down of BRD4 can both recruit the FADD and activate caspases. The sensitization did not regulate the death receptors DR4 and DR5. Moreover, BRD4 inhibition can block TRAIL-induced IKK activation by suppressing the transcriptional activity of NF-κB. These findings indicate that targeting combination therapy with TRAIL and BRD4 inhibitors can be a promising strategy to overcome TRAIL resistance in NSCLC.
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spelling pubmed-83644642021-08-15 BRD4 inhibition promotes TRAIL-induced apoptosis by suppressing the transcriptional activity of NF-κB in NSCLC Shi, Liu Xiong, Yu Hu, Xiaoyan Wang, Zhihao Xie, Conghua Int J Med Sci Research Paper Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and agonistic antibodies against TRAIL death receptors (DR) can induce apoptosis preferentially in tumor cells while causing virtually no damage to normal cells. However, their therapeutic potential is limited by occurring resistance in tumor cells, including non-small cell lung cancer (NSCLC). Thus, elucidation of the molecular targets and signaling pathways responsible for TRAIL resistance is imperative for devising effective therapeutic strategies for TRAIL resistant cancers. In the present study, we demonstrated that inhibition of Bromodomain-containing protein 4 (BRD4) or genetic knock-down of BRD4, an epigenetic reader and master transcription coactivator, can sensitize lung cancer cells to TRAIL. This sensitization is in a caspase-dependent manner. Inhibition of BRD4 by small molecule inhibitor (+)-JQ-1 and genetic knock-down of BRD4 can both recruit the FADD and activate caspases. The sensitization did not regulate the death receptors DR4 and DR5. Moreover, BRD4 inhibition can block TRAIL-induced IKK activation by suppressing the transcriptional activity of NF-κB. These findings indicate that targeting combination therapy with TRAIL and BRD4 inhibitors can be a promising strategy to overcome TRAIL resistance in NSCLC. Ivyspring International Publisher 2021-06-26 /pmc/articles/PMC8364464/ /pubmed/34400879 http://dx.doi.org/10.7150/ijms.60776 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Shi, Liu
Xiong, Yu
Hu, Xiaoyan
Wang, Zhihao
Xie, Conghua
BRD4 inhibition promotes TRAIL-induced apoptosis by suppressing the transcriptional activity of NF-κB in NSCLC
title BRD4 inhibition promotes TRAIL-induced apoptosis by suppressing the transcriptional activity of NF-κB in NSCLC
title_full BRD4 inhibition promotes TRAIL-induced apoptosis by suppressing the transcriptional activity of NF-κB in NSCLC
title_fullStr BRD4 inhibition promotes TRAIL-induced apoptosis by suppressing the transcriptional activity of NF-κB in NSCLC
title_full_unstemmed BRD4 inhibition promotes TRAIL-induced apoptosis by suppressing the transcriptional activity of NF-κB in NSCLC
title_short BRD4 inhibition promotes TRAIL-induced apoptosis by suppressing the transcriptional activity of NF-κB in NSCLC
title_sort brd4 inhibition promotes trail-induced apoptosis by suppressing the transcriptional activity of nf-κb in nsclc
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364464/
https://www.ncbi.nlm.nih.gov/pubmed/34400879
http://dx.doi.org/10.7150/ijms.60776
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