Cysteine depletion induces pancreatic tumor ferroptosis in mice. Badgley, M. A., Kremer, D. M., Maurer, H. C., DelGiorno, K. E., Lee, H., Purohit, V., Sagalovskiy, I. R., Ma, A., Kapilian, J., Firl, C. E. M., Decker, A. R., Sastra, S. A., Palermo, C. F., Andrade, L. R., Sajjakulnukit, P., Zhang, L., Tolstyka, Z. P., Hirschhorn, T., Lamb, C., Liu, T., Gu, W., Seeley, E. S., Stone, E., Georgiou, G., Manor, U., Iuga, A., Wahl, G. M., Stockwell, B. R., Lyssiotis, C. A., & Olive, K. P. Science, 368(6486):85-89, 2020.
Cysteine depletion induces pancreatic tumor ferroptosis in mice [link]Paper  doi  abstract   bibtex   
Cell death can occur through different mechanisms, several of which are being explored as potential targets for cancer treatment. One form of cell death that has attracted recent interest is ferroptosis, which is triggered by high intracellular levels of lipid reactive oxygen species. Pancreatic cancer cells have high levels of reactive oxygen species but manage to avoid ferroptosis by importing extracellular cysteine. Studying mice bearing pancreatic tumors, Badgley et al. found that administration of a drug inhibiting cysteine import induced tumor-selective ferroptosis and inhibited tumor growth. Further work will be required to determine whether this therapeutic strategy will be effective in human pancreatic cancer, a tumor type for which new treatments are urgently needed. Science, this issue p. 85 A drug that lowers intracellular cysteine levels inhibits growth of pancreatic tumors in mice by inducing a specific form of cell death. Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system xC– is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system xC– subunit, Slc7a11, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.
@article{doi:10.1126/science.aaw9872,
  author = {Michael A. Badgley  and Daniel M. Kremer  and H. Carlo Maurer  and Kathleen E. DelGiorno  and Ho-Joon Lee  and Vinee Purohit  and Irina R. Sagalovskiy  and Alice Ma  and Jonathan Kapilian  and Christina E. M. Firl  and Amanda R. Decker  and Steve A. Sastra  and Carmine F. Palermo  and Leonardo R. Andrade  and Peter Sajjakulnukit  and Li Zhang  and Zachary P. Tolstyka  and Tal Hirschhorn  and Candice Lamb  and Tong Liu  and Wei Gu  and E. Scott Seeley  and Everett Stone  and George Georgiou  and Uri Manor  and Alina Iuga  and Geoffrey M. Wahl  and Brent R. Stockwell  and Costas A. Lyssiotis  and Kenneth P. Olive },
  title = {Cysteine depletion induces pancreatic tumor ferroptosis in mice},
  journal = {Science},
  volume = {368},
  number = {6486},
  pages = {85-89},
  year = {2020},
  doi = {10.1126/science.aaw9872},
  URL = {https://www.science.org/doi/abs/10.1126/science.aaw9872},
  eprint = {https://www.science.org/doi/pdf/10.1126/science.aaw9872},
  abstract = {Cell death can occur through different mechanisms, several of which are being explored as potential targets for cancer treatment. One form of cell death that has attracted recent interest is ferroptosis, which is triggered by high intracellular levels of lipid reactive oxygen species. Pancreatic cancer cells have high levels of reactive oxygen species but manage to avoid ferroptosis by importing extracellular cysteine. Studying mice bearing pancreatic tumors, Badgley et al. found that administration of a drug inhibiting cysteine import induced tumor-selective ferroptosis and inhibited tumor growth. Further work will be required to determine whether this therapeutic strategy will be effective in human pancreatic cancer, a tumor type for which new treatments are urgently needed. Science, this issue p. 85 A drug that lowers intracellular cysteine levels inhibits growth of pancreatic tumors in mice by inducing a specific form of cell death. Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system xC– is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system xC– subunit, Slc7a11, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.}
}
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