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.
Highlights
Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of death [1,2]
The expression of endogenous reactive oxygen species modulator-1 (Romo1) was elevated in colorectal cancer cell lines comparing normal colon cell lines (Figure S1)
We found that the Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cell death was remarkably increased in Romo1 knockdown (Figure 1B)
Summary
Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of death [1,2]. Despite the emergence of new treatments for colorectal cancer, new treatment options are still limited [1]. TNF-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF). TRAIL activates apoptosis in a wide range of cancer cells through interaction with the death receptors [3]. It does not show cytotoxicity in normal cells. In this regard, TRAIL is a promising new biological anticancer drug [4,5]. Despite the tumor-killing potential of TRAIL, TRAIL therapy has major limitations, namely a short half-life and the existence of TRAIL-resistant cancer populations.
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