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

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.