ArticleClinical cancer research : an official journal of the American Association for Cancer Research2015
Methionine Deprivation Induces a Targetable Vulnerability in Triple-Negative Breast Cancer Cells by Enhancing TRAIL Receptor-2 Expression.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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66 citing papers in PubMed, 110 citations in OpenAlex.
- Role of methionine metabolism in cancer: recent advances in molecular mechanisms and therapeutic implications.Experimental hematology & oncology · 2026Review
- Methionine restriction for cancer therapy: From preclinical studies to clinical trials.Cancer pathogenesis and therapy · 2026Review
- Identification of disease ameliorated metabolite candidates from Gut Microbes and their interacting targets based on a novel estimating function.Frontiers in microbiology · 2026Article
- Metabolic Reprogramming in Retinoblastoma Patients: Treatment Naïve Active Retinoblastoma Versus Regressed Tumors Post-Treatment.Investigative ophthalmology & visual science · 2025Article
- Amino acid metabolism in breast cancer: pathogenic drivers and therapeutic opportunities.Protein & cell · 2025Review
- Methionine Dependency and Restriction in Cancer: Exploring the Pathogenic Function and Therapeutic Potential.Pharmaceuticals (Basel, Switzerland) · 2025Review
- A whole food, plant-based diet reduces amino acid levels in patients with metastatic breast cancer.Cancer & metabolism · 2024Article
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- A whole food, plant-based diet reduces amino acid levels in patients with metastatic breast cancer.medRxiv : the preprint server for health sciences · 2024Article
- The Role of Amino Acids in the Diagnosis, Risk Assessment, and Treatment of Breast Cancer: A Review.Current issues in molecular biology · 2023Review
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- Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade.Nature communications · 2023Article
- Dietary Manipulation of Amino Acids for Cancer Therapy.Nutrients · 2023Review
- SLC43A2 and NFκB signaling pathway regulate methionine/cystine restriction-induced ferroptosis in esophageal squamous cell carcinoma via a feedback loop.Cell death & disease · 2023Article
- Study on the mechanism of oral administration of tetrandrine during neoadjuvant chemotherapy for colon cancer.Oncology letters · 2023Article
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- mTORC1-c-Myc pathway rewires methionine metabolism for HCC progression through suppressing SIRT4 mediated ADP ribosylation of MAT2A.Cell & bioscience · 2022Article
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- Action and function of helicases on RNA G-quadruplexes.Methods (San Diego, Calif.) · 2022Review
6 more citing papers are in PubMed but not listed here.
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4 authors at 1 institution in 1 country.
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Abstract
purposeMany neoplasms are vulnerable to methionine deficiency by mechanisms that are poorly understood. Because gene profiling studies have revealed that methionine depletion increases TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) mRNA, we postulated that methionine stress sensitizes breast cancer cells to proapoptotic TRAIL-R2 agonists. EXPERIMENTAL
designHuman triple (ER/PR/HER2)-negative breast carcinoma cell lines were cultured in control or methionine-free media. The effects of methionine depletion on TRAIL receptor expression and sensitivity to chemotherapy or a humanized agonistic TRAIL-R2 monoclonal antibody (lexatumumab) were determined. The melanoma-associated antigen MAGED2 was silenced to delineate its functional role in sensitizing TNBC cells to methionine stress. An orthotopic TNBC model was utilized to evaluate the effects of dietary methionine deficiency, lexatumumab, or the combination.
resultsMethionine depletion sensitized TNBC cells to lexatumumab-induced caspase activation and apoptosis by increasing TRAIL-R2 mRNA and cell surface expression. MCF-10A cells transformed by oncogenic H-Ras, but not untransformed cells, and matrix-detached TNBC cells were highly sensitive to the combination of lexatumumab and methionine depletion. Proteomics analyses revealed that MAGED2, which has been reported to reduce TRAIL-R2 expression, was suppressed by methionine stress. Silencing MAGED2 recapitulated features of methionine deprivation, including enhanced mRNA and cell surface expression of TRAIL receptors and increased sensitivity to TRAIL receptor agonists. Dietary methionine deprivation enhanced the antitumor effects of lexatumumab in an orthotopic metastatic TNBC model.
conclusionsMethionine depletion exposes a targetable defect in TNBC cells by increasing TRAIL-R2 expression. Our findings provide the foundation for a clinical trial combining dietary methionine restriction and TRAIL-R2 agonists. Clin Cancer Res; 21(12); 2780-91. ©2015 AACR.
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