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  1. Article ; Online: Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine.

    Poursaitidis, Ioannis / Wang, Xiaomeng / Crighton, Thomas / Labuschagne, Christiaan / Mason, David / Cramer, Shira L / Triplett, Kendra / Roy, Rajat / Pardo, Olivier E / Seckl, Michael J / Rowlinson, Scott W / Stone, Everett / Lamb, Richard F

    Cell reports

    2017  Volume 18, Issue 11, Page(s) 2547–2556

    Abstract: Cancer cells reprogram their metabolism, altering both uptake and utilization of extracellular nutrients. We individually depleted amino acid nutrients from isogenic cells expressing commonly activated oncogenes to identify correspondences between ... ...

    Abstract Cancer cells reprogram their metabolism, altering both uptake and utilization of extracellular nutrients. We individually depleted amino acid nutrients from isogenic cells expressing commonly activated oncogenes to identify correspondences between nutrient supply and viability. In HME (human mammary epithelial) cells, deprivation of cystine led to increased cell death in cells expressing an activated epidermal growth factor receptor (EGFR) mutant. Cell death occurred via synchronous ferroptosis, with generation of reactive oxygen species (ROS). Hydrogen peroxide promoted cell death, as both catalase and inhibition of NADPH oxidase 4 (NOX4) blocked ferroptosis. Blockade of EGFR or mitogen-activated protein kinase (MAPK) signaling similarly protected cells from ferroptosis, whereas treatment of xenografts derived from EGFR mutant non-small-cell lung cancer (NSCLC) with a cystine-depleting enzyme inhibited tumor growth in mice. Collectively, our results identify a potentially exploitable sensitization of some EGFR/MAPK-driven tumors to ferroptosis following cystine depletion.
    Language English
    Publishing date 2017-03-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2017.02.054
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine

    Ioannis Poursaitidis / Xiaomeng Wang / Thomas Crighton / Christiaan Labuschagne / David Mason / Shira L. Cramer / Kendra Triplett / Rajat Roy / Olivier E. Pardo / Michael J. Seckl / Scott W. Rowlinson / Everett Stone / Richard F. Lamb

    Cell Reports, Vol 18, Iss 11, Pp 2547-

    2017  Volume 2556

    Abstract: Cancer cells reprogram their metabolism, altering both uptake and utilization of extracellular nutrients. We individually depleted amino acid nutrients from isogenic cells expressing commonly activated oncogenes to identify correspondences between ... ...

    Abstract Cancer cells reprogram their metabolism, altering both uptake and utilization of extracellular nutrients. We individually depleted amino acid nutrients from isogenic cells expressing commonly activated oncogenes to identify correspondences between nutrient supply and viability. In HME (human mammary epithelial) cells, deprivation of cystine led to increased cell death in cells expressing an activated epidermal growth factor receptor (EGFR) mutant. Cell death occurred via synchronous ferroptosis, with generation of reactive oxygen species (ROS). Hydrogen peroxide promoted cell death, as both catalase and inhibition of NADPH oxidase 4 (NOX4) blocked ferroptosis. Blockade of EGFR or mitogen-activated protein kinase (MAPK) signaling similarly protected cells from ferroptosis, whereas treatment of xenografts derived from EGFR mutant non-small-cell lung cancer (NSCLC) with a cystine-depleting enzyme inhibited tumor growth in mice. Collectively, our results identify a potentially exploitable sensitization of some EGFR/MAPK-driven tumors to ferroptosis following cystine depletion.
    Keywords ferroptosis ; oncogene ; EGFR ; ROS ; MAPK ; GPX4 ; NOX4 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2017-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth.

    Cramer, Shira L / Saha, Achinto / Liu, Jinyun / Tadi, Surendar / Tiziani, Stefano / Yan, Wupeng / Triplett, Kendra / Lamb, Candice / Alters, Susan E / Rowlinson, Scott / Zhang, Yan Jessie / Keating, Michael J / Huang, Peng / DiGiovanni, John / Georgiou, George / Stone, Everett

    Nature medicine

    2016  Volume 23, Issue 1, Page(s) 120–127

    Abstract: ... ROS, endogenous L-cysteine (L-Cys) production is insufficient for GSH synthesis. This necessitates ... uptake of L-Cys that is predominantly in its disulfide form, L-cystine (CSSC), via the xCT(-) transporter ... mediates sustained depletion of the extracellular L-Cys and CSSC pool in mice and non-human primates ...

    Abstract Cancer cells experience higher oxidative stress from reactive oxygen species (ROS) than do non-malignant cells because of genetic alterations and abnormal growth; as a result, maintenance of the antioxidant glutathione (GSH) is essential for their survival and proliferation. Under conditions of elevated ROS, endogenous L-cysteine (L-Cys) production is insufficient for GSH synthesis. This necessitates uptake of L-Cys that is predominantly in its disulfide form, L-cystine (CSSC), via the xCT(-) transporter. We show that administration of an engineered and pharmacologically optimized human cyst(e)inase enzyme mediates sustained depletion of the extracellular L-Cys and CSSC pool in mice and non-human primates. Treatment with this enzyme selectively causes cell cycle arrest and death in cancer cells due to depletion of intracellular GSH and ensuing elevated ROS; yet this treatment results in no apparent toxicities in mice even after months of continuous treatment. Cyst(e)inase suppressed the growth of prostate carcinoma allografts, reduced tumor growth in both prostate and breast cancer xenografts and doubled the median survival time of TCL1-Tg:p53
    MeSH term(s) Animals ; Blotting, Western ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Cystathionine gamma-Lyase/pharmacology ; Cysteine/drug effects ; Cysteine/metabolism ; Cystine/drug effects ; Cystine/metabolism ; Female ; Glutathione/metabolism ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Macaca fascicularis ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Neoplasm Transplantation ; Oxidative Stress ; Polyethylene Glycols/pharmacology ; Prostatic Neoplasms/metabolism ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/genetics
    Chemical Substances Reactive Oxygen Species ; Tumor Suppressor Protein p53 ; Polyethylene Glycols (3WJQ0SDW1A) ; Cystine (48TCX9A1VT) ; Cystathionine gamma-Lyase (EC 4.4.1.1) ; cyst(e)inase protein, human (EC 4.4.1.1) ; Glutathione (GAN16C9B8O) ; Cysteine (K848JZ4886)
    Language English
    Publishing date 2016-11-21
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/nm.4232
    Database MEDical Literature Analysis and Retrieval System OnLINE

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