ArticleCancer research2016
Cystine Deprivation Triggers Programmed Necrosis in VHL-Deficient Renal Cell Carcinomas.
Article in Cancer research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 86 citations in OpenAlex.
- The influence of low-carbohydrate diets on the metabolic response to androgen-deprivation therapy in prostate cancer.The Prostate · 2021Trial
- Metabolomic effects of androgen deprivation therapy treatment for prostate cancer.Cancer medicine · 2020Trial
- Necroptosis-related diseases are regulated by the unfolded protein response during endoplasmic reticulum stress.Genes & diseases · 2027Review
- The rise of reducing reagent-resistant TfR1 dimer marks ferroptosis.Nature cell biology · 2026Article
- Metformin Inhibits Ferroptotic Cell Death by Suppressing Cysteine Deprivation-Induced Mitochondrial Dysfunction.Pharmacology research & perspectives · 2026Article
- Bioinformatics analyses reveal the role of RIPK1 in clear cell renal cell carcinoma.BMC cancer · 2026Article
- Hydrogen sulphide alleviates depression-like behaviors by suppressing the hippocampal necroptosis-neuroinflammation-KP imbalance axis.Frontiers in pharmacology · 2025Article
- Cystine/cysteine metabolism regulates the progression and response to treatment of triple‑negative breast cancer (Review).Oncology letters · 2024Review
- Disulfidptosis, A Novel Cell Death Pathway: Molecular Landscape and Therapeutic Implications.Aging and disease · 2024Review
- Metabolic alterations in hereditary and sporadic renal cell carcinoma.Nature reviews. Nephrology · 2024Review
- Machine learning-driven prognostic analysis of cuproptosis and disulfidptosis-related lncRNAs in clear cell renal cell carcinoma: a step towards precision oncology.European journal of medical research · 2024Article
- Frontier knowledge and future directions of programmed cell death in clear cell renal cell carcinoma.Cell death discovery · 2024Review
- Therapeutic effects of natural compounds against diabetic complications via targeted modulation of ferroptosis.Frontiers in pharmacology · 2024Review
- Ferroptosis-associated genes and compounds in renal cell carcinoma.Frontiers in immunology · 2024Review
- Necroptosis-related genes are associated with prognostic features of kidney renal clear cell carcinoma.Discover oncology · 2023Article
- Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade.Nature communications · 2023Article
- Targeting ferroptosis in renal cell carcinoma: Potential mechanisms and novel therapeutics.Heliyon · 2023Review
- Environmental Determinants of Ferroptosis in Cancer.Cancers · 2023Review
- Hepatitis E virus infection remodels the mature tRNAome in macrophages to orchestrate NLRP3 inflammasome response.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Cellular and Molecular Players in the Tumor Microenvironment of Renal Cell Carcinoma.Journal of clinical medicine · 2023Review
4 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 1 institution in 2 countries.
Funding
Abstract
Oncogenic transformation may reprogram tumor metabolism and render cancer cells addicted to extracellular nutrients. Deprivation of these nutrients may therefore represent a therapeutic opportunity, but predicting which nutrients cancer cells become addicted remains difficult. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear cell renal cancer cells (ccRCC), with or without VHL, upon the deprivation of individual amino acids. We found that cystine deprivation triggered rapid programmed necrosis in VHL-deficient cell lines and primary ccRCC tumor cells, but not in VHL-restored counterparts. Blocking cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status, suggesting that metabolic responses alone are not sufficient to explain the observed distinct fates of VHL-deficient and restored cells. Instead, we found that increased levels of TNFα associated with VHL loss forced VHL-deficient cells to rely on intact RIPK1 to inhibit apoptosis. However, the preexisting elevation in TNFα expression rendered VHL-deficient cells susceptible to necrosis triggered by cystine deprivation. We further determined that reciprocal amplification of the Src-p38 (MAPK14)-Noxa (PMAIP1) signaling and TNFα-RIP1/3 (RIPK1/RIPK3)-MLKL necrosis pathways potentiated cystine-deprived necrosis. Together, our findings reveal that cystine deprivation in VHL-deficient RCCs presents an attractive therapeutic opportunity that may bypass the apoptosis-evading mechanisms characteristic of drug-resistant tumor cells. Cancer Res; 76(7); 1892-903. ©2016 AACR.
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