ArticleJCI insight2023
SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis.
Article in JCI insight, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 16 citations in OpenAlex.
- Epithelial SLC25A20 Deficiency Drives Immunosuppressive Neutrophil Remodeling via ARG1 Palmitoylation to Promote Colorectal Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Evaluating KRAS-Associated Responses to Sulfasalazine and 5-Fluorouracil in Colorectal Cancer Using Integrated 2D and PEGDA Microwell-Based 3D Tumor Models.International journal of molecular sciences · 2026Article
- SLC25A21 promotes ferroptosis by inducing mitochondrial GPX4 deficiency in colorectal cancer.Cellular and molecular life sciences : CMLS · 2026Article
- Unravelling Resistance: Integrating Metabolism, Epigenetics, Immunology, and Proteostasis in Strategies against Kirsten Rat Sarcoma Viral Oncogene Homolog-mutant Colorectal Cancer.International journal of biological sciences · 2026Review
- HDAC4 Promotes Cancer Stemness in Nonsmall Cell Lung Cancer by Upregulating SLC38A2 Expression via HIF-1α to Enhance Glutamine Metabolism.Analytical cellular pathology (Amsterdam) · 2026Article
- SLC25A11 Is Associated with KDM2A-Dependent Reduction in rRNA Transcription Induced by Aminooxyacetic Acid.Cells · 2025Article
- Discovery-Replication Strategy Identifies Serum Metabolite Biomarkers for Colorectal Cancer in a Chinese Cohort.Cancer science · 2025Article
- Single-cell sequencing insights into the transcriptional landscape of cerebral cavernous malformations.Angiogenesis · 2025Review
- Unveiling Metabolic Signatures as Potential Biomarkers in Common Cancers: Insights from Lung, Breast, Colorectal, Liver, and Gastric Tumours.Biomolecules · 2025Review
- Current status of traditional Chinese medicine in modulating mitochondrial metabolic abnormalities in tumors.Cancer biology & medicine · 2025Review
- Crosstalk Between Metabolic Reprogramming and Epigenetic Modifications in Colorectal Cancer: Mechanisms and Clinical Applications.Current issues in molecular biology · 2025Review
- Mitochondrial metabolic reprogramming in colorectal cancer: mechanisms of resistance and future clinical interventions.Cell death discovery · 2025Review
- Phosphorylation of POU3F3 Mediated Nuclear Translocation Promotes Proliferation in Non-Small Cell Lung Cancer through Accelerating ATP5PF Transcription and ATP Production.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Colorectal Cancer: Pathogenesis and Targeted Therapy.MedComm · 2025Review
- The roles of KRAS in cancer metabolism, tumor microenvironment and clinical therapy.Molecular cancer · 2025Review
- Glutamine metabolism and ammonia death: targeted modulation for enhanced cancer immunotherapy.Frontiers in immunology · 2025Review
- The Role of Mitochondrial Solute Carriers SLC25 in Cancer Metabolic Reprogramming: Current Insights and Future Perspectives.International journal of molecular sciences · 2024Review
- SLC25A21 correlates with the prognosis of adult acute myeloid leukemia through inhibiting the growth of leukemia cells via downregulating CXCL8.Cell death & disease · 2024Article
- Current research and future prospects of immunonutrition in gastrointestinal malignancies.Frontiers in immunology · 2024Review
- Cancer Therapeutic Potential and Prognostic Value of the SLC25 Mitochondrial Carrier Family: A Review.Cancer control : journal of the Moffitt Cancer CenterReview
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be a promising therapeutic strategy for KRAS-mutant CRC. However, the precise mechanism by which Gln metabolism reprogramming promotes and coordinates KRAS-mutant CRC progression remains to be fully investigated. Here, we discovered that solute carrier 25 member 21 (SLC25A21) expression was downregulated in KRAS-mutant CRC, and that SLC25A21 downregulation was correlated with poor survival of KRAS-mutant CRC patients. SLC25A21 depletion selectively accelerated the growth, invasion, migration, and metastasis of KRAS-mutant CRC cells in vitro and in vivo, and inhibited Gln-derived α-ketoglutarate (α-KG) efflux from mitochondria, thereby potentiating Gln replenishment, accompanied by increased GTP availability for persistent KRAS activation in KRAS-mutant CRC. The restoration of SLC25A21 expression impaired the KRAS-mutation-mediated resistance to cetuximab in KRAS-mutant CRC. Moreover, the arrested α-KG efflux that occurred in response to SLC25A21 depletion inhibited the activity of α-KG-dependent DNA demethylases, resulting in a further decrease in SLC25A21 expression. Our studies demonstrate that SLC25A21 plays a significant role as a tumor suppressor in KRAS-mutant CRC by antagonizing Gln-dependent anaplerosis to limit GTP availability for KRAS activation, which suggests potential alternative therapeutic strategies for KRAS-mutant CRC.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.