Pharmacologic inhibition of MEK and PI-3K converges on the mTOR/S6 pathway to decelerate cellular senescence

Inhibition of mTOR by rapamycin prevents cellular senescence. Here we investigated the effects of MEK and PI-3K on cellular senescence. Unlike LY294002 (PI-3K inhibitor), both U0126 and PD98059 (MEK inhibitors) did not significantly decrease beta-Gal staining in aging human fibroblasts and fibrosarc...

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Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Tex.), 2009-06, Vol.8 (12), p.1896-1900
Main Authors: Demidenko, Zoya N., Shtutman, Michael, Blagosklonny, Mikhail V
Format: Article
Language:English
Subjects:
Binding
Biology
Bioscience
Butadienes - pharmacology
Calcium
Cancer
Cell
Cell Line, Tumor
Cell Proliferation - drug effects
Cellular Senescence - drug effects
Cellular Senescence - physiology
Chromones - pharmacology
Cycle
Enzyme Inhibitors - pharmacology
Fibroblasts - drug effects
Fibroblasts - enzymology
Flavonoids - pharmacology
Humans
Landes
Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases - metabolism
Morpholines - pharmacology
Nitriles - pharmacology
Organogenesis
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphatidylinositol 3-Kinases - metabolism
Protein Kinases - drug effects
Protein Kinases - metabolism
Proteins
Sirolimus - pharmacology
TOR Serine-Threonine Kinases
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Summary:Inhibition of mTOR by rapamycin prevents cellular senescence. Here we investigated the effects of MEK and PI-3K on cellular senescence. Unlike LY294002 (PI-3K inhibitor), both U0126 and PD98059 (MEK inhibitors) did not significantly decrease beta-Gal staining in aging human fibroblasts and fibrosarcoma cells. However, using a sensitive, functional method, we identified that not only LY294002 but also U0126 prevented irreversible loss of proliferative potential associated with cellular senescence. At concentrations that blocked S6 phosphorylation, rapamycin, U0126 and LY294002 equally prevented senescence. Furthermore, there was no additive effect by combining of rapamycin with either U0126 or LY294002. Taken together this suggests that (a) simultaneous activation of PI-3K and MEK is required to ensure cellular senescence and (b) U0126 and LY294002 suppresses senescence via the rapamycin-sensitive pathway.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.8.12.8809