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

Autor: Xuejia Feng, Gui Yang, Litian Zhang, Shishi Tao, Joong Sup SHIM, Liang Chen, Qingxia Wu
Rok vydání: 2022
Předmět:
Zdroj: Investigational New Drugs. 40:1244-1253
ISSN: 1573-0646
0167-6997
DOI: 10.1007/s10637-022-01306-7
Popis: 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.
Databáze: OpenAIRE
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