Journal
JOURNAL OF BIOMOLECULAR SCREENING
Volume 16, Issue 6, Pages 603-617Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/1087057111406547
Keywords
embryonal carcinoma cell; embryonic stem cell; high-content screening; kinase inhibitors
Funding
- Biotechnology and Biological Sciences Research Council [BB/D006120/1] Funding Source: Medline
- Medical Research Council [G0700785] Funding Source: Medline
- Biotechnology and Biological Sciences Research Council [BB/D006120/1] Funding Source: researchfish
- Medical Research Council [G0700785] Funding Source: researchfish
- BBSRC [BB/D524908/1, BB/D006120/1] Funding Source: UKRI
- MRC [G0700785] Funding Source: UKRI
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Disentangling the complex interactions that govern stem cell fate choices of self-renewal, differentiation, or death presents a formidable challenge. Image-based phenotype-driven screening meets this challenge by providing means for rapid testing of many small molecules simultaneously. Pluripotent embryonal carcinoma (EC) cells offer a convenient substitute for embryonic stem (ES) cells in such screens because they are simpler to maintain and control. The authors developed an image-based screening assay to identify compounds that affect survival or differentiation of the human EC stem cell line NTERA2 by measuring the effect on cell number and the proportion of cells expressing a pluripotency-associated marker SSEA3. A pilot screen of 80 kinase inhibitors identified several compounds that improved cell survival or induced differentiation. The survival compounds Y-27632, HA-1077, and H-8 all strongly inhibit the kinases ROCK and PRK2, high-lighting the important role of these kinases in EC cell survival. Two molecules, GF109203x and rottlerin, induced EC differentiation. The effects of rottlerin were also investigated in human ES cells. Rottlerin inhibited the self-renewal ability of ES cells, caused the cell cycle arrest, and repressed the expression of pluripotency-associated genes. (Journal of Biomolecular Screening 2011; 16: 603-617)
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