ArticleRedox biology2024
RSL3 sensitizes glioma cells to ionizing radiation by suppressing TGM2-dependent DNA damage repair and epithelial-mesenchymal transition.
Article in Redox biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it.
- A comprehensive bibliometric analysis of ferroptosis in tumor resistance: development and emerging trends.Frontiers in immunology · 2025Pooled it
- Proton Radiation-Induced Cognitive Impairment via Disruption of Hippocampal Neuronal Mitophagic Homeostasis.Biomolecules · 2026Article
- Interaction of NDRG1 and TGM2 Modulates DNA Replication and Repair.Molecular cancer research : MCR · 2026Article
- Therapeutic effects of Icariside II on radiation cystitis: revealing the mechanistic role of the FN1/Itgαvβ6-PI3K/AKT signaling pathway using single-cell RNA sequencing.International journal of surgery (London, England) · 2026Article
- Targeting Ferroptosis in Glioblastoma: Molecular Mechanisms, Tumor Microenvironment, and Therapeutic Opportunities.Cancers · 2026Review
- OV16 Improves Radiation-Induced Intestinal Injury by Targeting Transglutaminase 2.Molecules (Basel, Switzerland) · 2026Article
- Inhibition of TGM2 enhances cisplatin sensitivity in MSH2-deficient bladder cancer.Cell death discovery · 2026Article
- Metabolic drivers of genome instability in cancer: mechanisms and therapeutic opportunities.Experimental hematology & oncology · 2026Review
- Reactive oxygen species in health and disease.Molecular biomedicine · 2026Review
- Inducing Ferroptosis: Sensitization Strategy for Radiotherapy and Its Application.Antioxidants (Basel, Switzerland) · 2026Review
- MBOAT1 Promotes Glioma Progression Through Enhancing Ferroptosis Resistance and Immunosuppressive Microenvironment.CNS neuroscience & therapeutics · 2026Article
- TGM2 Regulates Radiosensitivity via POGZ-Mediated Repair of DNA Double-Strand Breaks in Cervical Cancer.Cancer science · 2026Article
- TET1 as a master regulator controlling GPX4-dependent and -independent ferroptosis surveillance in acute myeloid leukemia.Nature communications · 2026Article
- RSL3 Promotes STAT3 Ubiquitination to Induce Autophagy and Apoptosis in PARPi-Resistant Breast Cancer Cells.Biomolecules · 2025Article
- Molecular characterization of macrophage-related prognostic factors in glioblastoma revealed by combined analysis on single-cell and bulk transcriptome data.Discover oncology · 2025Article
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5 authors.
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No grant is acknowledged in the PubMed record.
Abstract
RAS-selective lethal small molecule 3 (RSL3) is a small-molecule compound that triggers ferroptosis by inactivating glutathione peroxidase 4. However, its effect on the radioresistance of glioma cells and the underlying mechanisms remains unclear. In this study, we found that RSL3 sensitized glioma cells to ionizing radiation (IR) and enhanced IR-induced DNA double-strand breaks (DSBs). Inhibition of ferroptosis pathways partly prevented the clonogenic death caused by the IR/RSL3 combination but did not alleviate the DNA DSBs, indicating that RSL3 promotes IR-induced DNA DSBs via a non-ferroptotic mechanism. We demonstrated that transglutaminase 2 (TGM2) plays a vital role in the radiosensitization effect of RSL3 on glioma cells. Treatment with RSL3 downregulated TGM2 in a dose-dependent manner. Overexpression of TGM2 not only alleviated DNA DSBs but also inhibited clonogenic death caused by the IR/RSL3 combination. Mechanistically, RSL3 triggered oxidative stress in glioma cells, which promoted the S-gluthathionylation of TGM2 via upregulation of glutathione S-transferase P1(GSTP1), culminating in the proteasomal degradation of TGM2. This process resulted in the suppression of DNA repair mechanisms by impeding the nuclear accumulation of TGM2 and disrupting the interaction between TGM2 and topoisomerase IIα after irradiation. We also found that RSL3 inhibited glioma cell epithelial-mesenchymal transition (EMT) in both IR-treated and non-IR-treated cells. Overexpression of TGM2 prevented, while knockdown of TGM2 aggravated the EMT inhibition caused by RSL3, indicating that RSL3 also sensitized glioma cells to IR by inhibiting EMT via a TGM2-dependent mechanism. Furthermore, in mice bearing human U87 tumor xenografts, RSL3 administration synergized with IR to inhibit tumor growth, accompanied by TGM2 inhibition, DNA DSBs, and EMT inhibition in tumor tissues. Taken together, we demonstrated that RSL3 sensitizes glioma cells to IR by suppressing TGM2-mediated DNA repair and EMT.
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