TRIM59 guards ER proteostasis and prevents Bortezomib-mediated colorectal cancer (CRC) cells' killing

The endoplasmic reticulum (ER) is a critical organelle that preserves the protein homeostasis of cells. Under various stress conditions, cells evolve a degree of capacity to maintain ER proteostasis, which is usually augmented in tumor cells, including colorectal cancer (CRC) cells, to bolster their survival and resistance to apoptosis. Bortezomib (BTZ) is a promising drug used in CRC treatment; however, its main limitation result from drug resistance. Here, we identified the role of tripartite motif-containing protein 59 (TRIM59)-a protein localized on the ER membrane- in the prevention of BTZ-mediated CRC killing. Depletion of TRIM59 is associated with the enhancement of ER stress and a remarkable increase in unfolded protein response (UPR) signaling. Besides, TRIM59 strengthens ER-associated degradation (ERAD) and alleviates the generation of ROS. Of note, TRIM59 knockdown synergizes with the anti-cancer effect of BTZ both in vitro and in vivo. Our findings revealed a role for TRIM59 in the ER by guarding ER proteostasis and represents a novel therapeutic target of CRC.

Automated summary

This study identified the role of tripartite motif-containing protein 59 (TRIM59) in preventing drug resistance in colorectal cancer (CRC) cells treated with Bortezomib (BTZ). Depletion of TRIM59 enhances endoplasmic reticulum stress and unfolded protein response (UPR) signaling, while also strengthening endoplasmic reticulum-associated degradation (ERAD) and alleviating ROS generation. Knockdown of TRIM59 synergizes with the anti-cancer effect of BTZ both in vitro and in vivo.