MHY1485 activates mTOR and protects osteoblasts from dexamethasone.
Biochem Biophys Res Commun
; 481(3-4): 212-218, 2016 Dec 09.
Article
em En
| MEDLINE
| ID: mdl-27884298
ABSTRACT
Dexamethasone (Dex) exerts cytotoxic effects to cultured osteoblasts. The potential effect of MHY1485, a small-molecular mammalian target of rapamycin (mTOR) activator, against the process was studied here. In both osteoblastic MC3T3-E1 cells and primary murine osteoblasts, treatment with MHY1485 significantly ameliorated Dex-induced cell death and apoptosis. mTOR inhibition, through mTOR kinase inhibitor OSI-027 or mTOR shRNAs, abolished MHY1485-mediated osteoblast cytoprotection against Dex. Intriguingly, activation of mTOR complex (mTORC1), but not mTORC2, is required for MHY1485's anti-Dex activity. mTORC1 inhibitors (rapamycin and RAD001) or Raptor knockdown almost reversed MHY1485-induced osteoblast cytoprotection. mTORC2 inhibition, via shRNA knockdown of Rictor, failed to affect MHY1485's activity in MC3T3-E1 cells. Further studies showed that MHY1485 treatment in MC3T3-E1 cells and primary murine osteoblasts significantly inhibited Dex-induced mitochondrial death pathway activation, the latter was tested by mitochondrial depolarization, cyclophilin D-ANT-1 association and cytochrome C cytosol release. Together, these results suggest that MHY1485 activates mTORC1 signaling to protect osteoblasts from Dex.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Triazinas
/
Dexametasona
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Morfolinas
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Citoproteção
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Serina-Treonina Quinases TOR
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article