ArticleThe Journal of biological chemistry2011
Cancer cell survival following DNA damage-mediated premature senescence is regulated by mammalian target of rapamycin (mTOR)-dependent Inhibition of sirtuin 1.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 85 citations in OpenAlex.
- The Effects of Phosphorylation on the Structure and Function of Motif A, an Intrinsically Disordered Region within SIRT1.Biochemistry · 2026Article
- Epigenetic regulation and posttranslational modifications of FXR: underlying mechanisms and implications in digestive diseases.Acta pharmacologica Sinica · 2026Review
- The Effects of Phosphorylation on the Structure and Function of Motif A, an Intrinsically Disordered Region within SIRT1.bioRxiv : the preprint server for biology · 2026Article
- Inhibition of CDK5 signaling mediated inflammation in macrophages promotes cutaneous wound healing.Scientific reports · 2025Article
- Activation and inhibition of sirtuins: From bench to bedside.Medicinal research reviews · 2025Review
- Inhibitory protein-protein interactions of the SIRT1 deacetylase are choreographed by post-translational modification.Protein science : a publication of the Protein Society · 2024Article
- SIRT1 ubiquitination is regulated by opposing activities of APC/C-Cdh1 and AROS during stress-induced premature senescence.Experimental & molecular medicine · 2023Article
- Sporothrix globosa melanin regulates autophagy via the TLR2 signaling pathway in THP-1 macrophages.PLoS neglected tropical diseases · 2023Article
- A Mitochondrial Perspective on Noncommunicable Diseases.Biomedicines · 2023Review
- The phosphorylation to acetylation/methylation cascade in transcriptional regulation: how kinases regulate transcriptional activities of DNA/histone-modifying enzymes.Cell & bioscience · 2022Review
- Metabolic reprograming of MDSCs within tumor microenvironment and targeting for cancer immunotherapy.Acta pharmacologica Sinica · 2022Review
- Cancer treatment induces neuroinflammation and behavioral deficits in mice.Frontiers in behavioral neuroscience · 2022Article
- Regulation of yak longissimus lumborum energy metabolism and tenderness by the AMPK/SIRT1 signaling pathways during postmortem storage.PloS one · 2022Article
- Sorafenib, rapamycin, and venetoclax attenuate doxorubicin-induced senescence and promote apoptosis in HCT116 cells.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2022Article
- Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR activity modulation in innate immunity.iScience · 2021Article
- Post-translational regulation of autophagy is involved in intra-microbiome suppression of fungal pathogens.Microbiome · 2021Article
- Cannabidiol Induces Autophagy to Protects Neural Cells From Mitochondrial Dysfunction by Upregulating SIRT1 to Inhibits NF-κB and NOTCH Pathways.Frontiers in cellular neuroscience · 2021Article
- Autophagy attenuates high glucose-induced oxidative injury to lens epithelial cells.Bioscience reports · 2020Article
- mTOR may interact with PARP-1 to regulate visible light-induced parthanatos in photoreceptors.Cell communication and signaling : CCS · 2020Article
- Dynamic Metabolic Response to Adriamycin-Induced Senescence in Breast Cancer Cells.Metabolites · 2018Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
DNA-damaging agents can induce premature senescence in cancer cells, which contributes to the static effects of cancer. However, senescent cancer cells may re-enter the cell cycle and lead to tumor relapse. Understanding the mechanisms that control the viability of senescent cells may be helpful in eliminating these cells before they can regrow. Treating human squamous cell carcinoma (SCC) cells with the anti-cancer compounds, resveratrol and doxorubicin, triggered p53-independent premature senescence by invoking oxidative stress-mediated DNA damage. This process involved the mTOR-dependent phosphorylation of SIRT1 at serine 47, resulting in the inhibition of the deacetylase activity of SIRT1. SIRT1 phosphorylation caused concomitant increases in p65/RelA NF-κB acetylation and the expression of an anti-apoptotic Bfl-1/A1. SIRT1 physically interacts with the mTOR-Raptor complex, and a single amino acid substitution in the TOS (TOR signaling) motif in the SIRT1 prevented Ser-47 phosphorylation and Bfl-1/A1 induction. The pharmacologic and genetic inhibition of mTOR, unphosphorylatable S47A, or F474A TOS mutants restored SIRT1 deacetylase activity, blocked Bfl-1/A1 induction, and sensitized prematurely senescent SCC cells for apoptosis. We further show that the treatment of UVB-induced SCCs with doxorubicin transiently stabilized tumor growth but was followed by tumor regrowth upon drug removal in p53(+/-)/SKH-1 mice. The subsequent treatment of stabilized SCCs with rapamycin decreased tumor size and induced caspase-3 activation. These results demonstrate that the inhibition of SIRT1 by mTOR fosters survival of DNA damage-induced prematurely senescent SCC cells via Bfl-1/A1 in the absence of functional p53.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.