SIRT1 rescues autophagic flux via PI3K/AKT/mTOR inactivation to suppress DOX-induced senescence in MCF-7 cells

  • Exp Cell Res. 2025 Sep 1;452(1):114754. doi: 10.1016/j.yexcr.2025.114754.
Ge Wu  1 ,  Wei Yao  1 ,  Lin Cheng  1 ,  Xiaoping Wang  2 ,  Tongsheng Chen  3
Affiliations
  • 1. MOE Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China.
  • 2. Department of Pain Management, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China. Electronic address: [email protected].
  • 3. MOE Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China. Electronic address: [email protected].
PMID: 40962168 DOI: 10.1016/j.yexcr.2025.114754
Abstract

Sirtuin 1 (SIRT1), a deacetylase, has been extensively studied for its roles in regulating Autophagy, aging, cellular metabolism and tumorigenesis. In this study, we investigated how SIRT1 modulates doxorubicin (DOX)-induced senescence in MCF-7 cells, a breast Cancer cell line. SIRT1 significantly reduced the DOX-induced elevation of senescence-associated proteins p53, p21, and SA-β-Gal activity, revealing that SIRT1 inhibited DOX-induced senescence. Notably, SIRT1 increased the DOX-induced upregulation of p62 accumulation and reversed the DOX-induced decrease in the LC3II/LC3I ratio, revealing that SIRT1 reversed the DOX-induced blockage of autophagic flux. The Autophagy inhibitor chloroquine (CQ) partially abolished the Anti-aging effects of SIRT1, indicating that Autophagy mediated the Anti-aging effects of SIRT1. Additionally, SIRT1 suppressed the DOX-induced activation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, thereby facilitating Autophagy. The PI3K Inhibitor LY294002 enhanced the Anti-aging effect of SIRT1 which, however, was reversed by the Akt Activator SC-79. In conclusion, our study reveals that SIRT1 counteracts DOX-induced senescence in MCF-7 cells by inactivating PI3K/Akt/mTOR pathway.

Keywords
Autophagy; DOX; PI3K/AKT/mTOR; Senescence; Sirtuin 1.
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