期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 291, 期 19, 页码 10058-10066出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.701375
关键词
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资金
- National Institutes of Health, Frederick National Lab, Center for Cancer Research
- Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]
High-throughput screening of extracts from plants, marine, and micro-organisms led to the identification of the extract from the plant Phyttanthus engieri as the most potent inhibitor of EWS-FI.I1 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-13I after a transient up-regulation.
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