Nucleus-Translocated Gclm Promotes Chemoresistance in Colorectal Cancer Through a Moonlighting Function

Authors

Jin-Fei Lin
Ze-Xian Liu
Dong-Liang Chen
Ren-Ze Huang
Fen Cao
Kai Yu
Ting Li
Hai-Yu Mo
Hui Sheng
Zhi-Bing Liang
Kun Liao
Yi Han
Shan-Shan Li
Zhao-Lei Zeng
Song Gao
Huai-Qiang Ju
Rui-Hua Xu

Publication Date

1-2-2025

Journal

Nature Communications

Abstract

Metabolic enzymes perform moonlighting functions during tumor progression, including the modulation of chemoresistance. However, the underlying mechanisms of these functions remain elusive. Here, utilizing a metabolic clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 knockout library screen, we observe that the loss of glutamate-cysteine ligase modifier subunit (GCLM), a rate-limiting enzyme in glutathione biosynthesis, noticeably increases the sensitivity of colorectal cancer (CRC) cells to platinum-based chemotherapy. Mechanistically, we unveil a noncanonical mechanism through which nuclear GCLM competitively interacts with NF-kappa-B (NF-κB)-repressing factor (NKRF), to promote NF-κB activity and facilitate chemoresistance. In response to platinum drug treatment, GCLM is phosphorylated by P38 MAPK at T17, resulting in its recognition by importin a5 and subsequent nuclear translocation. Furthermore, elevated expression of nuclear GCLM and phospho-GCLM correlate with an unfavorable prognosis and poor benefit from standard chemotherapy. Overall, our work highlights the essential nonmetabolic role and posttranslational regulatory mechanism of GCLM in enhancing NF-κB activity and subsequent chemoresistance.

Keywords

Humans, Colorectal Neoplasms, Drug Resistance, Neoplasm, NF-kappa B, Cell Nucleus, Cell Line, Tumor, Glutamate-Cysteine Ligase, Phosphorylation, Animals, Antineoplastic Agents, Mice, Gene Expression Regulation, Neoplastic, p38 Mitogen-Activated Protein Kinases, Female, CRISPR-Cas Systems, Male, Active Transport, Cell Nucleus, Mice, Nude, Colon cancer, Chemotherapy, Phosphorylation

DOI

10.1038/s41467-024-55568-1

PMID

39747101

PMCID

PMC11696352

PubMedCentral® Posted Date

1-2-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes