2. Academic Validation
  3. Sirt3 activates autophagy to prevent DOX-induced senescence by inactivating PI3K/AKT/mTOR pathway in A549 cells

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

  • Biochim Biophys Acta Mol Cell Res. 2023 Feb;1870(2):119411. doi: 10.1016/j.bbamcr.2022.119411.
Xuhong Fan 1,  Yuting He 1,  Guihao Wu 1,  Hongce Chen 2,  Xuecheng Cheng 2,  Yongtong Zhan 1,  Chunchun An 2,  Tongsheng Chen 2,  Xiaoping Wang 3
Affiliations

Affiliations

  • 1 Department of Pain Management, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
  • 2 MOE Key Laboratory of Laser Life Science, Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
  • 3 Department of Pain Management, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China. Electronic address: [email protected].
PMID: 36521686 DOI: 10.1016/j.bbamcr.2022.119411
Abstract

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-β-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.

Keywords

Autophagy; PI3K/AKT/mTOR pathway; Senescence; Sirtuin 3.

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