A Phosphatidylinositol 3-Kinase Inhibitor Induces a Senescent-like Growth Arrest in Human Diploid Fibroblasts
AbstractThe signal transduction cascade initiated by the activation of phosphoinositide 3-kinase (PI-3 kinase) is implicated in mitogenic and antiapoptotic signaling generated by growth factors in a variety of cell types. We have examined the consequences of an inhibition of this pathway in human diploid fibroblasts. We find that a specific PI-3 kinase inhibitor (LY294002 ) causes growth arrest in these cells accompanied by changes in gene expression that are similar to those seen during cellular senescence. A second inhibitor, PD58029, which is specific for the mitogen-activated protein kinase kinase 1 (MEK-1), also induces a growth arrest but does not induce the same spectrum of gene expression. The pattern of gene expression in the presence the MEK-1 inhibitor is similar to that seen during growth arrest induced by serum starvation. The specific phenotypic changes seen following inhibition of PI-3 kinase are: an increase in ß-galactosidase activity; a decrease in EPC-1 gene expression; and a dramatic increase in collagenase gene expression. Thus, growth arrest with a PI-3 kinase inhibitor induces a senescent-like phenotype that is not seen when cells are growth arrested by either serum starvation or a MEK-1 inhibitor. 1 This work was supported by grants from the W. W. Smith Foundation and CA68923 to C. S. M. M. D. is supported by grant AG 00131-12, M. T. and V. J. C. are supported by grant AG 00378-25 to V. J. C. 2 To whom requests for reprints should be addressed, at Center for Gerontological Research, Department of Pathology and Laboratory Medicine, MCP-Hahnemann School of Medicine, Allegheny University, 2900 Queen Lane, Philadelphia, PA 19129. Phone: (215) 991-8468; Fax: (215) 843-1192; E-mail: Sell@auhs.edu.