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 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 suppress senescence via the rapamycin-sensitive pathway.
Demidenko
Zoya N
ZN
Oncotarget, Albany, NY, USA.
Shtutman
Michael
M
Blagosklonny
Mikhail V
MV
D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D020929:Mitogen-Activated Protein Kinase Kinases; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546842:MTOR protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one