Sirt3 activates autophagy to prevent DOX-induced senescence by inactivating PI3K/AKT/mTOR pathway in A549 cells

被引:24
作者
Fan, Xuhong [1 ]
He, Yuting [1 ]
Wu, Guihao [1 ]
Chen, Hongce [2 ]
Cheng, Xuecheng [2 ]
Zhan, Yongtong [1 ]
An, Chunchun [2 ]
Chen, Tongsheng [2 ]
Wang, Xiaoping [1 ]
机构
[1] Jinan Univ, Affiliated Hosp 1, Dept Pain Management, Guangzhou 510630, Peoples R China
[2] South China Normal Univ, Coll Biophoton, MOE Key Lab Laser Life Sci, Guangdong Prov Key Lab Laser Life Sci, Guangzhou 510631, Peoples R China
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH | 2023年 / 1870卷 / 02期
基金
中国国家自然科学基金;
关键词
Sirtuin; 3; Autophagy; Senescence; PI3K; AKT; mTOR pathway; OXIDATIVE STRESS; PREMATURE SENESCENCE; MITOCHONDRIAL DYSFUNCTION; CARDIOMYOCYTE DEATH; FREE-RADICALS; CANCER-CELLS; DOXORUBICIN; APOPTOSIS; INHIBITION; SURVIVAL;
D O I
10.1016/j.bbamcr.2022.119411
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Sirtuin 3 (Sirt3), a mitochondrial deacetylase, regulates mitochondrial redox homeostasis and autophagy and is involved in physiological and pathological processes such as aging, cellular metabolism, and tumorigenesis. We here investigate how Sirt3 regulates doxorubicin (DOX)-induced senescence in lung cancer A549 cells. Sirt3 greatly reduced DOX-induced upregulation of senescence marker proteins p53, p16, p21 and SA-& beta;-Gal activity as well as ROS levels. Notably, Sirt3 reversed DOX-induced autophagic flux blockage, as shown by increased p62 degradation and LC3II/LC3I ratio. Importantly, the autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) partially abolished the antioxidant stress and antiaging effects of Sirt3, while the autophagy activator rapamycin (Rap) potentiated these effects of Sirt3, demonstrating that autophagy mediates the anti-aging effects of Sirt3. Additionally, Sirt3 inhibited the DOX-induced activation of the phosphatidylinositol-3-kinase (PI3K)/ AKT/mammalian target of rapamycin (mTOR) signaling pathway, which in turn activated autophagy. The PI3K inhibitor LY294002 promoted the antioxidant stress and antiaging effects of Sirt3, while the AKT activator SC-79 reversed these effects of Sirt3. Taken together, Sirt3 counteracts DOX-induced senescence by improving autophagic flux.
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页数:11
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