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Englerin A Inhibits EWS-FLI1 DNA Binding in Ewing Sarcoma Cells

  1. Author:
    Caropreso, V.
    Darvishi, E.
    Turbyville, T. J.
    Ratnayake, R.
    Grohar, P. J.
    McMahon, J. B.
    Woldemichael, G. M.

  2. Author Address

    From the Molecular Targets Laboratory, NCI, National Institutes of Health.;Optical Microscopy and Analysis Laboratory, Leidos Biomedical Research, Inc., and.;Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, Michigan 49503, and Division of Hematology/Oncology, Helen DeVos Children's Hospital, Grand Rapids, Michigan 49503.;Basic Science Program, Leidos Biomedical Research, Inc., Molecular Targets Laboratory, Frederick National Laboratory, Frederick, Maryland 21702, woldemichaelg@mail.nih.gov.
    1. Year: 2016
    2. Date: 6-May
    3. Epub Date: 3/11/2016
  2. Journal: The Journal of biological chemistry
    1. 291
    2. 19
    3. Pages: 10058-66
  4. Type of Article: Article
  5. ISSN: 0021-9258 (Print);0021-9258
  1. Abstract:

    High-throughput screening of extracts from plants, marine, and micro-organisms led to the identification of the extract from the plant Phyllanthus engleri as the most potent inhibitor of EWS-FLI1 induced luciferase reporter expression. Testing of compounds isolated from this extract in turn led to the identification of Englerin A (EA) as the active constituent of the extract. EA induced both necrosis and apoptosis in Ewing cells subsequent to a G2M accumulation of cells in the cell cycle. It also impacted clonogenic survival and anchorage-independent proliferation while also decreasing the proportion of chemotherapy-resistant cells identified by high ALDH activity. EA also caused a sustained increase in cytosolic calcium levels. EA appears to exert its effect on Ewing cells through a decrease in phosphorylation of EWS-FLI1 and its ability to bind DNA. This effect is mediated, at least in part, through a decrease in the levels of the calcium-dependent protein kinase PKC-betaI after a transient up-regulation.

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  2. DOI: 10.1074/jbc.M115.701375
  3. PMID: 26961871
  4. PMCID: PMC4858959

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