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Romo1 Inhibition Induces TRAIL-Mediated Apoptosis in Colorectal Cancer

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to behave as an attractive anti-cancer agent in various cancers. Despite its promise TRAIL has limitations such as short half-life and rapid development of resistance. In this regard, approaches to sensitizers of TRAIL that can...

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Autores principales: Jo, Min Jee, Kim, Bu Gyeom, Park, Seong Hye, Kim, Hong Jun, Jeong, Soyeon, Kim, Bo Ram, Kim, Jung Lim, Na, Yoo Jin, Jeong, Yoon A., Yun, Hye Kyeong, Kim, Dae Yeong, Han, Jeongsu, Heo, Jun Young, Yoo, Young Do, Lee, Dae-Hee, Oh, Sang Cheul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565722/
https://www.ncbi.nlm.nih.gov/pubmed/32825500
http://dx.doi.org/10.3390/cancers12092358
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author Jo, Min Jee
Kim, Bu Gyeom
Park, Seong Hye
Kim, Hong Jun
Jeong, Soyeon
Kim, Bo Ram
Kim, Jung Lim
Na, Yoo Jin
Jeong, Yoon A.
Yun, Hye Kyeong
Kim, Dae Yeong
Han, Jeongsu
Heo, Jun Young
Yoo, Young Do
Lee, Dae-Hee
Oh, Sang Cheul
author_facet Jo, Min Jee
Kim, Bu Gyeom
Park, Seong Hye
Kim, Hong Jun
Jeong, Soyeon
Kim, Bo Ram
Kim, Jung Lim
Na, Yoo Jin
Jeong, Yoon A.
Yun, Hye Kyeong
Kim, Dae Yeong
Han, Jeongsu
Heo, Jun Young
Yoo, Young Do
Lee, Dae-Hee
Oh, Sang Cheul
author_sort Jo, Min Jee
collection PubMed
description Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to behave as an attractive anti-cancer agent in various cancers. Despite its promise TRAIL has limitations such as short half-life and rapid development of resistance. In this regard, approaches to sensitizers of TRAIL that can overcome the limitations of TRAIL are necessary. However, the molecular targets and mechanisms underlying sensitization to TRAIL-induced apoptosis are not fully understood. Here, we propose that reactive oxygen species modulator-1 (Romo1) as an attractive sensitizer of TRAIL. Romo1 is a mitochondrial inner membrane channel protein that controls reactive oxygen species (ROS) production, and its expression is highly upregulated in various cancers, including colorectal cancer. In the present study, we demonstrated that Romo1 inhibition significantly increased TRAIL-induced apoptosis of colorectal cancer cells, but not of normal colon cells. The combined effect of TRAIL and Romo1 inhibition was correlated with the activation of mitochondrial apoptosis pathways. Romo1 silencing elevated the protein levels of BCL-2-associated X protein (Bax) by downregulating the ubiquitin proteasome system (UPS). Romo1 inhibition downregulated the interaction between Bax and Parkin. Furthermore, Romo1 knockdown triggered the mitochondrial dysfunction and ROS generation. We validated the effect of combination in tumor xenograft model in vivo. In conclusion, our study demonstrates that Romo1 inhibition induces TRAIL-mediated apoptosis by identifying the novel mechanism associated with the Bax/Parkin interaction. We suggest that targeting of Romo1 is essential for the treatment of colorectal cancer and may be a new therapeutic approach in the future and contribute to the drug discovery.
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spelling pubmed-75657222020-10-26 Romo1 Inhibition Induces TRAIL-Mediated Apoptosis in Colorectal Cancer Jo, Min Jee Kim, Bu Gyeom Park, Seong Hye Kim, Hong Jun Jeong, Soyeon Kim, Bo Ram Kim, Jung Lim Na, Yoo Jin Jeong, Yoon A. Yun, Hye Kyeong Kim, Dae Yeong Han, Jeongsu Heo, Jun Young Yoo, Young Do Lee, Dae-Hee Oh, Sang Cheul Cancers (Basel) Article Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to behave as an attractive anti-cancer agent in various cancers. Despite its promise TRAIL has limitations such as short half-life and rapid development of resistance. In this regard, approaches to sensitizers of TRAIL that can overcome the limitations of TRAIL are necessary. However, the molecular targets and mechanisms underlying sensitization to TRAIL-induced apoptosis are not fully understood. Here, we propose that reactive oxygen species modulator-1 (Romo1) as an attractive sensitizer of TRAIL. Romo1 is a mitochondrial inner membrane channel protein that controls reactive oxygen species (ROS) production, and its expression is highly upregulated in various cancers, including colorectal cancer. In the present study, we demonstrated that Romo1 inhibition significantly increased TRAIL-induced apoptosis of colorectal cancer cells, but not of normal colon cells. The combined effect of TRAIL and Romo1 inhibition was correlated with the activation of mitochondrial apoptosis pathways. Romo1 silencing elevated the protein levels of BCL-2-associated X protein (Bax) by downregulating the ubiquitin proteasome system (UPS). Romo1 inhibition downregulated the interaction between Bax and Parkin. Furthermore, Romo1 knockdown triggered the mitochondrial dysfunction and ROS generation. We validated the effect of combination in tumor xenograft model in vivo. In conclusion, our study demonstrates that Romo1 inhibition induces TRAIL-mediated apoptosis by identifying the novel mechanism associated with the Bax/Parkin interaction. We suggest that targeting of Romo1 is essential for the treatment of colorectal cancer and may be a new therapeutic approach in the future and contribute to the drug discovery. MDPI 2020-08-20 /pmc/articles/PMC7565722/ /pubmed/32825500 http://dx.doi.org/10.3390/cancers12092358 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jo, Min Jee
Kim, Bu Gyeom
Park, Seong Hye
Kim, Hong Jun
Jeong, Soyeon
Kim, Bo Ram
Kim, Jung Lim
Na, Yoo Jin
Jeong, Yoon A.
Yun, Hye Kyeong
Kim, Dae Yeong
Han, Jeongsu
Heo, Jun Young
Yoo, Young Do
Lee, Dae-Hee
Oh, Sang Cheul
Romo1 Inhibition Induces TRAIL-Mediated Apoptosis in Colorectal Cancer
title Romo1 Inhibition Induces TRAIL-Mediated Apoptosis in Colorectal Cancer
title_full Romo1 Inhibition Induces TRAIL-Mediated Apoptosis in Colorectal Cancer
title_fullStr Romo1 Inhibition Induces TRAIL-Mediated Apoptosis in Colorectal Cancer
title_full_unstemmed Romo1 Inhibition Induces TRAIL-Mediated Apoptosis in Colorectal Cancer
title_short Romo1 Inhibition Induces TRAIL-Mediated Apoptosis in Colorectal Cancer
title_sort romo1 inhibition induces trail-mediated apoptosis in colorectal cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565722/
https://www.ncbi.nlm.nih.gov/pubmed/32825500
http://dx.doi.org/10.3390/cancers12092358
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