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

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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.

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Abbreviations

ATF6α:

Activating transcription factor 6 alpha.

BTZ:

Bortezomib.

CHX:

Cycloheximide.

CRC:

Colorectal cancer.

E3s:

Ubiquitin ligases.

ER:

Endoplasmic reticulum.

ERAD:

Endoplasmic reticulum-associated degradation.

H2-DCFDA:

2’, 7’-dichlorodihydrofluorescein-diacetate.

IHC:

Immunohistochemistry.

IRE1:

Inositol-requiring kinase 1.

PERK:

Protein kinase RNA (PKR)-like ER kinase.

ROS:

Reactive oxygen species.

RT:

Room temperature.

TRIMs:

Tripartite motif-containing family proteins.

UPR:

Unfolded protein response.

UPS:

Ubiquitin-proteasome system.

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Funding

This research was supported by Natural Science Foundation of Guangdong Province (2022A1515012030), Joint Funds of the Natural Science Foundation of Shandong Province (ZR2021LSW024), and the National Key R&D Program of China (2020YFA0710802).

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Author notes

  1. Xuejia Feng, Gui Yang, and Litian Zhang contributed equally to this work.

Authors and Affiliations

  1. Key laboratory of clinical veterinary medicine in Tibet, Tibet Agriculture and Animal Husbandry College, 860000, Linzhi, Tibet, People’s Republic of China

    Xuejia Feng & Qingxia Wu

  2. Shenzhen Laboratory of Tumor Cell Biology, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 518055, Shenzhen, P. R. China

    Xuejia Feng, Litian Zhang, Shishi Tao & Liang Chen

  3. Department of Otolaryngology, Longgang Central Hospital, 518055, Shenzhen, P. R. China

    Gui Yang

  4. Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China

    Shishi Tao & Joong Sup SHIM

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  1. Xuejia Feng
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Contributions

X.F., G.Y., L.Z., S.T., S.J.S., L.C.and Q.W. contributed to the acquisition of data, interpretation of data, and drafting the article. X.F., G.Y., L.Z., L.C. and Q.W. contributed to analyze the data and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Liang Chen or Qingxia Wu.

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Feng, X., Yang, G., Zhang, L. et al. TRIM59 guards ER proteostasis and prevents Bortezomib-mediated colorectal cancer (CRC) cells’ killing. Invest New Drugs 40, 1244–1253 (2022). https://doi.org/10.1007/s10637-022-01306-7

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