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Bitler BG , Fink LS , Wei Z , Peterson JR , Zhang RG
A High-Content Screening Assay for Small-Molecule Modulators of Oncogene-Induced Senescence
Journal of Biomolecular Screening. 2013 Oct;18(9) :1054-1061
PMID: WOS:000324760300010   
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Abstract
Cellular senescence is a state of stable cell growth arrest. Activation of oncogenes such as RAS in mammalian cells typically triggers cellular senescence. Oncogene-induced senescence (OIS) is an important tumor suppression mechanism, and suppression of OIS contributes to cell transformation. Oncogenes trigger senescence through a multitude of incompletely understood downstream signaling events that frequently involve protein kinases. To identify target proteins required for RAS-induced senescence, we developed a small-molecule screen in primary human fibroblasts undergoing senescence induced by oncogenic RAS (H-Ras(G12V)). Using a high-content imaging system to monitor two hallmarks of senescence, senescence-associated -galactosidase activity expression and inhibition of proliferation, we screened a library of known small-molecule kinase inhibitors for those that suppressed OIS. Identified compounds were subsequently validated and confirmed using a third marker of senescence, senescence-associated heterochromatin foci. In summary, we have established a novel high-content screening platform that may be useful for elucidating signaling pathways mediating OIS by targeting critical pathway components.
Notes
Bitler, Benjamin G. Fink, Lauren S. Wei, Zhi Peterson, Jeffrey R. Zhang, Rugang