Differential effects on cell motility, embryonic stem cell self-renewal and senescence by diverse Src kinase family inhibitors

• Published in: Experimental cell research 2012-02, Vol.318 (4), p.336-349
• Main Authors: Tamm, Christoffer, Galitó, Sara Pijuan, Annerén, Cecilia
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; APPROXIMATIONS; Aurora kinase; Cell culture; CELL CULTURES; Cell division; Cell migration; Cell Movement - drug effects; Cell Movement - genetics; CELL PROLIFERATION; Cell Proliferation - drug effects; Cells, Cultured; Cellular biology; Cellular Senescence - drug effects; Cellular Senescence - genetics; Colonies; Contact inhibition; Cross-selectivity; Differentiation; Embryo cells; Embryo, Mammalian; Embryonic stem cells; Embryonic Stem Cells - drug effects; Embryonic Stem Cells - metabolism; Embryonic Stem Cells - physiology; Epithelial cells; FIBROBLASTS; Indoles - pharmacology; INHIBITION; Kinases; MICE; Mice, Knockout; MITOSIS; Molecular biology; Molecular modelling; NIH 3T3 Cells; PD173952; PHOSPHOTRANSFERASES; PP2; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Proto-Oncogene Proteins c-fyn - antagonists & inhibitors; Proto-Oncogene Proteins c-fyn - genetics; Proto-Oncogene Proteins c-yes - antagonists & inhibitors; Proto-Oncogene Proteins c-yes - genetics; Proto-Oncogene Proteins pp60(c-src) - antagonists & inhibitors; Proto-Oncogene Proteins pp60(c-src) - genetics; Pyrimidines - pharmacology; RECEPTORS; Rodents; Senescence; Src kinase; Src protein; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - genetics; STEM CELLS; SU6656; Sulfonamides - pharmacology; TYROSINE
• ISSN: 0014-4827; 1090-2422; 1090-2422
• DOI: 10.1016/j.yexcr.2011.12.008

The Src family of non-receptor tyrosine kinases (SFKs) has been shown to play an intricate role in embryonic stem (ES) cell maintenance. In the present study we have focused on the underlying molecular mechanisms responsible for the vastly different effects induced by various commonly used SFK inhibitors. We show that several diverse cell types, including fibroblasts completely lacking SFKs, cannot undergo mitosis in response to SU6656 and that this is caused by an unselective inhibition of Aurora kinases. In contrast, PP2 and PD173952 block motility immediately upon exposure and forces cells to grow in dense colonies. The subsequent halt in proliferation of fibroblast and epithelial cells in the center of the colonies approximately 24 h post-treatment appears to be caused by cell-to-cell contact inhibition rather than a direct effect of SFK kinase inhibition. Interestingly, in addition to generating more homogenous and dense ES cell cultures, without any diverse effect on proliferation, PP2 and PD173652 also promote ES cell self-renewal by reducing the small amount of spontaneous differentiation typically observed under standard ES cell culture conditions. These effects could not be mirrored by the use of Gleevec, a potent inhibitor of c-Abl and PDGFR kinases that are also inhibited by PP2. ► SFK inhibitor SU6656 induces senescence in mouse ES cells. ► SU6656 inhibits mitosis in a SFK-independent manner via cross-selectivity for Aurora kinases. ► SFK inhibitor PP2 impairs cell motility in various cell lines, including mouse ES cells. ► Ensuing impeded motility, PP2 inhibits proliferation of various cells lines except for mouse ES cells. ► SFK inhibitors PP2 and PD173952 impede spontaneous differentiation in standard mouse ES culture maintenance.