Romo1 inhibition induces trail-mediated apoptosis in colorectal cancer

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number2358
Pages (from-to)1-18
Number of pages18
JournalCancers
Volume12
Issue number9
DOIs
Publication statusPublished - 2020 Sep

Keywords

  • Bax
  • Mitochondrial dysfunction
  • Parkin
  • Reactive oxygen species modulator-1
  • Tumor necrosis factor-related apoptosis-inducing ligand

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Jo, M. J., Kim, B. G., Park, S. H., Kim, H. J., Jeong, S., Kim, B. R., Kim, J. L., Na, Y. J., Jeong, Y. A., Yun, H. K., Kim, D. Y., Han, J., Heo, J. Y., Yoo, Y. D., Lee, D. H., & Oh, S. C. (2020). Romo1 inhibition induces trail-mediated apoptosis in colorectal cancer. Cancers, 12(9), 1-18. [2358]. https://doi.org/10.3390/cancers12092358