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...
Main Authors: | , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2020-08-01
|
Series: | Cancers |
Subjects: | |
Online Access: | https://www.mdpi.com/2072-6694/12/9/2358 |
id |
doaj-3db7e64d509f4caab9fcebf0a5590f23 |
---|---|
record_format |
Article |
spelling |
doaj-3db7e64d509f4caab9fcebf0a5590f232020-11-25T03:40:47ZengMDPI AGCancers2072-66942020-08-01122358235810.3390/cancers12092358Romo1 Inhibition Induces TRAIL-Mediated Apoptosis in Colorectal CancerMin Jee Jo0Bu Gyeom Kim1Seong Hye Park2Hong Jun Kim3Soyeon Jeong4Bo Ram Kim5Jung Lim Kim6Yoo Jin Na7Yoon A. Jeong8Hye Kyeong Yun9Dae Yeong Kim10Jeongsu Han11Jun Young Heo12Young Do Yoo13Dae-Hee Lee14Sang Cheul Oh15Department of Oncology, Korea University Guro Hospital, Seoul 08308, KoreaDepartment of Oncology, Korea University Guro Hospital, Seoul 08308, KoreaDepartment of Oncology, Korea University Guro Hospital, Seoul 08308, KoreaGraduate School of Medicine, Korea University College of Medicine, Seoul 02842, KoreaDepartment of Oncology, Korea University Guro Hospital, Seoul 08308, KoreaDepartment of Oncology, Korea University Guro Hospital, Seoul 08308, KoreaDepartment of Oncology, Korea University Guro Hospital, Seoul 08308, KoreaDepartment of Oncology, Korea University Guro Hospital, Seoul 08308, KoreaDepartment of Oncology, Korea University Guro Hospital, Seoul 08308, KoreaDepartment of Oncology, Korea University Guro Hospital, Seoul 08308, KoreaDepartment of Oncology, Korea University Guro Hospital, Seoul 08308, KoreaDepartment of Medical Science, School of Medicine, Chung-nam National University, Daejeon 35015, KoreaDepartment of Medical Science, School of Medicine, Chung-nam National University, Daejeon 35015, KoreaLaboratory of Molecular Cell Biology, Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul 02842, KoreaDepartment of Oncology, Korea University Guro Hospital, Seoul 08308, KoreaDepartment of Oncology, Korea University Guro Hospital, Seoul 08308, KoreaTumor 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 <i>in vivo</i>. 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.https://www.mdpi.com/2072-6694/12/9/2358reactive oxygen species modulator-1tumor necrosis factor-related apoptosis-inducing ligandBaxParkinmitochondrial dysfunction |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Min Jee Jo Bu Gyeom Kim Seong Hye Park Hong Jun Kim Soyeon Jeong Bo Ram Kim Jung Lim Kim Yoo Jin Na Yoon A. Jeong Hye Kyeong Yun Dae Yeong Kim Jeongsu Han Jun Young Heo Young Do Yoo Dae-Hee Lee Sang Cheul Oh |
spellingShingle |
Min Jee Jo Bu Gyeom Kim Seong Hye Park Hong Jun Kim Soyeon Jeong Bo Ram Kim Jung Lim Kim Yoo Jin Na Yoon A. Jeong Hye Kyeong Yun Dae Yeong Kim Jeongsu Han Jun Young Heo Young Do Yoo Dae-Hee Lee Sang Cheul Oh Romo1 Inhibition Induces TRAIL-Mediated Apoptosis in Colorectal Cancer Cancers reactive oxygen species modulator-1 tumor necrosis factor-related apoptosis-inducing ligand Bax Parkin mitochondrial dysfunction |
author_facet |
Min Jee Jo Bu Gyeom Kim Seong Hye Park Hong Jun Kim Soyeon Jeong Bo Ram Kim Jung Lim Kim Yoo Jin Na Yoon A. Jeong Hye Kyeong Yun Dae Yeong Kim Jeongsu Han Jun Young Heo Young Do Yoo Dae-Hee Lee Sang Cheul Oh |
author_sort |
Min Jee Jo |
title |
Romo1 Inhibition Induces TRAIL-Mediated Apoptosis in Colorectal Cancer |
title_short |
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_sort |
romo1 inhibition induces trail-mediated apoptosis in colorectal cancer |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-08-01 |
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 <i>in vivo</i>. 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. |
topic |
reactive oxygen species modulator-1 tumor necrosis factor-related apoptosis-inducing ligand Bax Parkin mitochondrial dysfunction |
url |
https://www.mdpi.com/2072-6694/12/9/2358 |
work_keys_str_mv |
AT minjeejo romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT bugyeomkim romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT seonghyepark romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT hongjunkim romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT soyeonjeong romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT boramkim romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT junglimkim romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT yoojinna romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT yoonajeong romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT hyekyeongyun romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT daeyeongkim romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT jeongsuhan romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT junyoungheo romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT youngdoyoo romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT daeheelee romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer AT sangcheuloh romo1inhibitioninducestrailmediatedapoptosisincolorectalcancer |
_version_ |
1724532931987243008 |