A phosphatidylinositol 3-kinase inhibitor induces a senescent-like growth arrest in human diploid fibroblasts

• Published in: Cancer research (Chicago, Ill.) Vol. 58; no. 1; pp. 1 - 4
• Main Authors: TRESINI, M, MAWAL-DEWAN, M, CRISTOFALO, V. J, SELL, C
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 1998
• Subjects: Ageing, cell death; beta-Galactosidase - antagonists & inhibitors; beta-Galactosidase - metabolism; Biological and medical sciences; Cell Division - drug effects; Cell physiology; Cells, Cultured; Cellular Senescence - drug effects; Chromones - pharmacology; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - physiology; Fundamental and applied biological sciences. Psychology; Humans; Mitogen-Activated Protein Kinase Kinases; Molecular and cellular biology; Morpholines - pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Protein Kinase Inhibitors; Human; Cell proliferation; Senescence; Enzyme; Transferases; Ageing; Enzyme inhibitor; Gene expression; In vitro; 1-Phosphatidylinositol 3-kinase; Signal transduction; Protein kinase; Established cell line; Fibroblast; Growth inhibitory factor
• ISSN: 0008-5472; 1538-7445

The 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 beta-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.