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J Biol Chem. 2016 May 6;291(19):10058-66. doi: 10.1074/jbc.M115.701375. Epub 2016 Mar 9.

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

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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,


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-βI after a transient up-regulation.


DNA-binding protein; EWS-FLI1; Englerin A; Ewings sarcoma; calcium; inhibition mechanism; inhibitor; transcription factor

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