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. 2022 Dec;40(6):1244-1253.
doi: 10.1007/s10637-022-01306-7. Epub 2022 Oct 28.

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

Xuejia Feng #  1   2 , Gui Yang #  3 , Litian Zhang #  2 , Shishi Tao  2   4 , Joong Sup Shim  4 , Liang Chen  5 , Qingxia Wu  6
Affiliations

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

Xuejia Feng et al. Invest New Drugs. 2022 Dec.

Abstract

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.

Keywords: Bortezomib; Colorectal cancer; ER-associated degradation; ER-stress; TRIM59; Unfolded protein response.

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