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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.

Author information

1
From the Molecular Targets Laboratory, NCI, National Institutes of Health.
2
Optical Microscopy and Analysis Laboratory, Leidos Biomedical Research, Inc., and.
3
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.
4
Basic Science Program, Leidos Biomedical Research, Inc., Molecular Targets Laboratory, Frederick National Laboratory, Frederick, Maryland 21702, woldemichaelg@mail.nih.gov.

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-βI after a transient up-regulation.

KEYWORDS:

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

PMID:
26961871
PMCID:
PMC4858959
DOI:
10.1074/jbc.M115.701375
[Indexed for MEDLINE]
Free PMC Article

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