ArticleNature communications2025
Nucleus-translocated GCLM promotes chemoresistance in colorectal cancer through a moonlighting function.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Anti-myeloma mechanisms of the selective NF-κB inhibitor QNZ.Molecular therapy. Oncology · 2026Article
- Kaempferol suppresses fibroblast-like synoviocyte proliferation in rheumatoid arthritis by targeting glutamate-cysteine ligase modifier subunit to inhibit ferroptosis resistance.Bone & joint research · 2026Article
- Tertiary lymphoid structure-related genes drive tumor microenvironment heterogeneity and prognostic disparities in left-Translational cancer research · 2026Article
- TRIM26-mediated NKRF degradation drives Osimertinib resistance through SNRPD2-dependent stress granule formation in lung adenocarcinoma.Cell death & disease · 2026Article
- Andrographolide Modulates Fibrogenic and Oxidative Stress Responses in Human Lung Fibroblasts.The Kaohsiung journal of medical sciences · 2026Article
- [Tumor-secreted dentin sialophosphoprotein induces oxaliplatin resistance in colorectal cancer through an integrin αvβ3-dependent pathway].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2026Article
- Nuclear-Cytoplasmic Axis in Cancer: From Protein Mislocalization to Anticancer Drug Resistance.Oncology research · 2026Review
- β-Lapachone sensitizes glioblastoma to Temozolomide by inhibiting NF-κB signaling.Functional & integrative genomics · 2025Article
- Deacetylation of TALDO1 by HDAC6 promotes glycolysis and nasopharyngeal carcinoma progression through a moonlighting function.Cell death & disease · 2025Article
- Immunometabolism: crosstalk with tumor metabolism and implications for cancer immunotherapy.Molecular cancer · 2025Review
- PANoptosis in cancer: bridging molecular mechanisms to therapeutic innovations.Cellular & molecular immunology · 2025Review
- The impact of oxidative stress and the NRF2-KEAP1-ARE signaling pathway on anticancer drug resistance.Oncology research · 2025Review
- Article
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Authors and funding
17 authors.
Funding
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.
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