Experimental cell researchSep 17, 2025

SIRT1 helps restore cell cleanup processes by turning off PI3K/AKT/mTOR to reduce doxorubicin-induced aging in breast cancer cells

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 7, 2026

Abstract

SIRT1 significantly reduced the DOX-induced elevation of senescence-associated proteins in MCF-7 breast cancer cells.

SIRT1 inhibited the increase of proteins associated with cellular aging, such as p53 and p21, induced by doxorubicin (DOX).
SIRT1 increased the accumulation of p62 and reversed the decrease in the ratio of LC3II to LC3I, suggesting a restoration of autophagic activity.
The anti-aging effects of SIRT1 were partially diminished by chloroquine, indicating that autophagy plays a role in these effects.
SIRT1 suppressed the activation of the PI3K/AKT/mTOR signaling pathway, which is known to influence growth and metabolism.
The PI3K inhibitor LY294002 enhanced the anti-aging effects of SIRT1, while activation of AKT counteracted these benefits.

Simplified

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.

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Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

PubMed

SIRT1 helps restore cell cleanup processes by turning off PI3K/AKT/mTOR to reduce doxorubicin-induced aging in breast cancer cells

Abstract

Full Text

Funding

Competing interests

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