AMPK alleviates oxidative stress-induced premature senescence via inhibition of NF-κB/STAT3 axis-mediated positive feedback loop
AMPK alleviates oxidative stress-induced premature senescence via inhibition of NF-κB/STAT3 axis-mediated positive feedback loop
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AMPK 通过抑制 NF-kappa B/STAT3 轴介导的正反馈环来缓解氧化应激引起的过早衰老
DOI：
10.1016/j.mad.2020.111347
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发表时间：
2020-10-01
影响因子：
5.3
通讯作者：
Gou, Xingchun
中科院分区：
文献类型：
--
作者：
Han, Xiaojuan;Zhang, Tianying;Gou, Xingchun
应激诱导的早衰(SiPS)的特征是分泌多种炎性细胞因子、趋化因子和蛋白水解酶，统称为衰老相关分泌表型(SASP)。AMPK的激活有助于预防SIPs，AMPK对SASP的影响可能包括在内，但这一现象的调控机制尚未阐明。在本研究中，我们发现SIPs伴随着核因子-kappaB活性的动态波动，这诱导了SASP的产生，同时增强和放大了局部的STAT3信号，从而促进了下游的衰老。核因子-kappaB和STAT3抑制剂以时间依赖的方式减轻氧化应激诱导的衰老。富含SASP因子的衰老细胞的条件培养液(CM)可以诱导健康细胞的生长停滞和促进衰老；相应地，STAT3抑制剂拮抗SASP诱导的衰老，表明通过支持SASP产生和促进衰老的NF-kappa B/STAT3途径实现正反馈机制。此外，我们还证实了AMPK负性调节SASP的产生和衰老发育与抑制核因子-kappa B/STAT3相关。综上所述，我们的结果表明，AMPK通过抑制NF-kappa B/SASP/STAT3信号介导的正反馈回路来防止氧化应激诱导的衰老发育。
Stress-induced premature senescence (SIPS) is characterized by the secretion of a variety of inflammatory cytokines, chemokines, and proteases, which are defined collectively as the senescence-associated secretory phenotype (SASP). AMP-activated protein kinase (AMPK) activation contributes to SIPS prevention, and the impact of AMPK on SASP may be included, but the mechanisms governing this phenomenon have not elucidated. In this study, we showed that SIPS is accompanied by a dynamic fluctuation of NF-kappa B activation, which induces SASP production, whilst reinforcing and amplifying local STAT3 signalling and subsequently enhancing downstream senescence. NF-kappa B and STAT3 inhibitors attenuate oxidative stress-induced senescence in a time-dependent manner. Conditioned medium (CM) from senescent cells rich in SASP factors can induce growth arrest and promote senescence in healthy cells; accordingly, a STAT3 inhibitor blunts the SASP-induced senescence, indicating a positive feedback mechanism via the NF-kappa B/STAT3 pathway that sustains SASP production and promotes senescence. In addition, we confirmed that AMPK negatively regulates SASP production and senescence development associated with NF-kappa B/STAT3 inhibition. In summary, our results suggest that AMPK prevents oxidative stress-induced senescence development via inhibiting the NF-kappa B/SASP/STAT3 signalling mediated positive feedback loop.