期刊
ARCHIVES OF TOXICOLOGY
卷 92, 期 2, 页码 679-692出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-017-2070-2
关键词
Dexamethasone; p21(Waf1/Cip1); MC3T3-E1 cells; Apoptosis; Nrf2/HO-1
类别
资金
- National Natural Science Foundation of China [31572587, 31272623, 3151101034]
Dexamethasone (Dex), a glucocorticoid with strong anti-inflammatory and immunosuppressive activities, has been shown to exhibit marked cytotoxicity and apoptosis in osteoblasts, but the underlying mechanisms have not yet been comprehensively investigated. P21(Waf1/Cip1) (p21) plays a critical role in the regulation of cell cycle progression and apoptosis. The present study aims to investigate the role of p21 in Dex-induced apoptosis in osteoblastic MC3T3-E1 cells, and to explore its mechanisms. Results demonstrated that Dex-induced apoptosis decreased the phosphorylation of Akt in a concentration-dependent manner. Moreover, LY294002, an inhibitor of the PI3K/Akt pathway enhanced the Dex-induced apoptosis of osteoblasts. On the contrary, insulin-like growth factor-1 (IGF-1), an activator of PI3K/Akt, attenuated the apoptosis of Dex in MC3T3-E1 cells. The protein level of p21 was downregulated by shortening its half-life, which was associated with inhibition of the PI3K/Akt pathway by Dex. Furthermore, depletion of p21 by siRNA enhanced Dex-induced caspase-3 activation and ROS generation, and promoted apoptosis of MC3T3-E1 cells. In addition, suppression of p21 led to a reduction of Dex-induced upregulation of nuclear Nrf2 and heme oxygenase-1 (HO-1) protein levels. These findings demonstrate that p21 depletion promotes Dex-induced apoptosis of MC3T3-E1 cells by inhibiting the antioxidant Nrf2/HO-1 pathway, which highlights the anti-apoptotic effect of p21 in MC3T3-E1 cells.
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