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    Fumarate hydratase inactivation in hereditary leiomyomatosis and renal cell cancer is synthetic lethal with ferroptosis induction

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    Author
    Kerins, Michael J.
    Milligan, John
    Wohlschlegel, James A.
    Ooi, Aikseng
    Affiliation
    Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol
    Issue Date
    2018-09
    Keywords
    ferroptosis
    fumarate hydratase
    GPX4
    hereditary leiomyomatosis and renal cell cancer
    synthetic lethal
    
    Metadata
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    Publisher
    WILEY
    Citation
    Kerins MJ, Milligan J, Wohlschlegel JA, Ooi A. Fumarate hydratase inactivation in hereditary leiomyomatosis and renal cell cancer is synthetic lethal with ferroptosis induction. Cancer Sci. 2018;109:2757–2766. https://doi.org/10.1111/cas.13701
    Journal
    CANCER SCIENCE
    Rights
    © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome characterized by inactivation of the Krebs cycle enzyme fumarate hydratase (FH). HLRCC patients are at high risk of developing kidney cancer of type 2 papillary morphology that is refractory to current radiotherapy, immunotherapy and chemotherapy. Hence, an effective therapy for this deadly form of cancer is urgently needed. Here, we show that FH inactivation (FH-/-) proves synthetic lethal with inducers of ferroptosis, an iron-dependent and nonapoptotic form of cell death. Specifically, we identified gene signatures for compound sensitivities based on drug responses for 9 different drug classes against the NCI-60 cell lines. These signatures predicted that ferroptosis inducers would be selectively toxic to FH-/- cell line UOK262. Preferential cell death against UOK262-FH-/- was confirmed with 4 different ferroptosis inducers. Mechanistically, the FH-/- sensitivity to ferroptosis is attributed to dysfunctional GPX4, the primary cellular defender against ferroptosis. We identified that C93 of GPX4 is readily post-translationally modified by fumarates that accumulate in conditions of FH-/-, and that C93 modification represses GPX4 activity. Induction of ferroptosis in FH-inactivated tumors represents an opportunity for synthetic lethality in cancer.
    Note
    Open access journal.
    ISSN
    13479032
    PubMed ID
    29917289
    DOI
    10.1111/cas.13701
    Version
    Final published version
    Sponsors
    National Science Foundation [DGE-1143953]; NIEHS [R21ES027920]
    Additional Links
    http://doi.wiley.com/10.1111/cas.13701
    ae974a485f413a2113503eed53cd6c53
    10.1111/cas.13701
    Scopus Count
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    UA Faculty Publications

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