Dexamethasone-induced apoptosis and up-regulation of Bim is dependent on glycogen synthase kinase-3.
Glucocorticoids are commonly used in the treatment of lymphoid malignancies. In this study, we show that apoptosis induced by dexamethasone (Dex), a synthetic glucocorticoid, was dependent on mitochondria, since overexpression of Bcl-X(L) prevented Dex-induced apoptotic changes. Dominant negative (DN) caspase-9 also prevented Dex-induced apoptotic changes including the loss of mitochondrial membrane potential indicating that caspase-9 controls mitochondrial changes. In addition, we evaluated the role of glycogen synthase kinase (GSK3) in Dex-induced apoptosis. Inhibition of GSK3 attenuated Dex-induced up-regulation of Bim, loss of mitochondrial membrane potential, release of cyt c and DNA fragmentation. These results indicate that GSK3 contributes to Dex-induced apoptosis by controlling up-regulation of Bim.
Nuutinen
Ulla
U
Department of Clinical Microbiology, Institute of Clinical Medicine, University of Kuopio, Yliopistonranta 1 C, 70210 Kuopio, Finland. ulla-maija.nuutinen@uku.fi
Ropponen
Antti
A
Suoranta
Sanna
S
Eeva
Jonna
J
Eray
Mine
M
Pellinen
Riikka
R
Wahlfors
Jarmo
J
Pelkonen
Jukka
J
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008224:Lymphoma, Follicular / Q000473:pathology; D008301:Maleimides / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects*; D051020:bcl-X Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D007211:Indoles; D008301:Maleimides; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C417521:SB 216763; D051020:bcl-X Protein; D003907:Dexamethasone; D038362:Glycogen Synthase Kinase 3