SIRT1-mediated FoxOs pathways protect against apoptosis by promoting autophagy in osteoblast-like MC3T3-E1 cells exposed to sodium fluoride.
SIRT1-mediated FoxOs pathways protect against apoptosis by promoting autophagy in osteoblast-like MC3T3-E1 cells exposed to sodium fluoride.
复制标题
SIRT1 介导的 FoxOs 通路通过促进暴露于氟化钠的成骨细胞样 MC3T3-E1 细胞的自噬来防止细胞凋亡
DOI：
10.18632/oncotarget.11573
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发表时间：
2016-10-04
期刊：
影响因子：
--
通讯作者：
Han B
中科院分区：
文献类型：
--
作者：
Gu X;Han D;Chen W;Zhang L;Lin Q;Gao J;Fanning S;Han B
氟可能导致牙齿、骨骼和其他身体组织的损害，是一个严重的公共卫生问题。SIRT 1使FOXO去乙酰化，从而促进或抑制细胞凋亡和自噬。氟可诱导细胞凋亡，但自噬在氟诱导细胞凋亡中的作用尚不清楚，SIRT 1与FOXO的相互作用有待进一步阐明。因此，本研究探讨NaF通过激活或抑制SIRT 1在体外诱导成骨样MC 3 T3-E1细胞凋亡和自噬的机制。通过RT-PCR、Western blot、流式细胞术、荧光显微镜和激光共聚焦显微镜观察，发现NaF可诱导细胞凋亡和自噬。结果还显示NaF以剂量依赖性方式上调SIRT 1的表达。当与SIRT 1激活剂SRT 1720孵育时，MC 3 T3-E1的自噬也间接上调，而凋亡显著减弱。当使用SIRT 1抑制剂Ex-527时，后者的作用被逆转。此外，SIRT 1还能增加FoxO 1的去乙酰化，促进其靶底物Rab 7的上调，以及FoxO 3的底物Bnip 3的上调，我们推测这些途径可能导致自噬通量的增加和凋亡的减少。总之，SIRT 1诱导的自噬增强通过在MC 3 T3-E1细胞中诱导自噬来保护氟诱导的凋亡，这可能与SIRT 1-FoxO 1-Rab 7轴和SIRT 1-FoxO 3-Binp 3轴相关。SIRT 1在细胞存活和死亡之间选择的作用为氟中毒提供了潜在的治疗策略。
Fluorine may result in damage to teeth, bones and other body tissues, and is a serious public health problem. SIRT1 deacetylates FOXOs, which brings about apoptosis and autophagy promotion or suppression. Fluorine may induce cell apoptosis, however, the role of autophagy in apoptosis induced by fluorine is still poorly understood, and the interaction between SIRT1 and FOXOs should be further illustrated. Therefore, this study investigated the mechanisms underlying the NaF- induced apoptosis and autophagy in osteoblast-like MC3T3-E1 cells in vitro through activating or inhibiting SIRT1. Via RT-PCR, western blot, flow cytometry assays, fluorescence and laser confocal microscopy, it was found that NaF induced both cell apoptosis and autophagy. Results also showed that NaF up-regulated SIRT1 expression in a dose-dependent manner. The autophagy of MC3T3-E1 was also up- regulated indirectly whilst apoptosis was significantly attenuated when incubated with the SIRT1 activator SRT1720. When SIRT1 inhibitor Ex-527 was used, the latter effects were reversed. Furthermore, SIRT1 increased deacetylation of FoxO1 and promoted the up-regulation of its target substrate Rab7, as well as increase of Bnip3 which was substrate of FoxO3, and we hypothesize that these pathways may cause an increase in autophagic flux and a reduction in apoptosis. In conclusion, SIRT1-induced autophagy enhancement protects against fluoride-induced apoptosis through autophagy induction in MC3T3-E1 cells, which may be associated with a SIRT1-FoxO1-Rab7 axis and a SIRT1-FoxO3-Binp3 axis. The role of SIRT1 in selecting between cell survival and death provides a potential therapeutic strategy in fluorosis.