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Cited by 124Telomeres, Telomerase, and SenescenceCancer, Lipids, and MetabolismGenetics, Aging, and Longevity in Model Organisms

Simvastatin suppresses breast cancer cell proliferation induced by senescent cells

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Liu, Su, Uppal, Harpreet, Demaria, Marco, Desprez, Pierre-Yves, Campisi, Judith, Kapahi, Pankaj·2015·Scientific Reports
DOI 10.1038/srep17895PMC PMC4677323
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Abstract

Cellular senescence suppresses cancer by preventing the proliferation of damaged cells, but senescent cells can also promote cancer though the pro-inflammatory senescence-associated secretory phenotype (SASP). Simvastatin, an HMG-coA reductase inhibitor, is known to attenuate inflammation and prevent certain cancers. Here, we show that simvastatin decreases the SASP of senescent human fibroblasts by inhibiting protein prenylation, without affecting the senescent growth arrest. The Rho family GTPases Rac1 and Cdc42 were activated in senescent cells and simvastatin reduced both activities. Further, geranylgeranyl transferase, Rac1 or Cdc42 depletion reduced IL-6 secretion by senescent cells. We also show that simvastatin mitigates the effects of senescent conditioned media on breast cancer cell proliferation and endocrine resistance. Our findings identify a novel activity of simvastatin and mechanism of SASP regulation. They also suggest that senescent cells, which accumulate after radio/chemo therapy, promote endocrine resistance in breast cancer and that simvastatin might suppress this resistance.

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  • Neutralizing antibodies against key SASP components or their receptors, including IL-6, IL-1α, IL-1β, and TNF, have demonstrated senomorphic effects.

    “A number of neutralizing antibodies directed against key components of the SASP or their receptors, including IL-6, IL-1α, IL-1β and TNF, also have shown senomorphic properties104,240–248 (TABLE 1).”

    From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [240]

    In Results (section ‘Simvastatin suppresses SASP-induced activation of the ERK pathway in breast cancer cells’; page unavailable), an anti-IL-6 antibody slightly reduced the effect of senescent-cell conditioned medium on breast cancer cell proliferation and ERK-pathway activation. The paper does not show that the antibody changes the SASP or other properties of senescent cells, nor does it test neutralizing antibodies against IL-1α, IL-1β, TNF, or their receptors. Its evidence for SASP suppression in senescent cells concerns simvastatin, not those antibodies. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Liu, S., Uppal, H., Demaria, M., Desprez, P.-Y., Campisi, J., & Kapahi, P.
Affiliations
  • Buck Institute for Research on Aging (US)
  • Santa Rosa Junior College (US)
Corresponding author
  • Campisi, Judith
  • Kapahi, Pankaj
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2015-12-14
Volume
5
Issue
1
Pages
17895-17895
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep17895
PMC
PMC4677323
OpenAlex
W2403350024
Cited by
124
References
14
Citations by year
2026: 8 · 2025: 17 · 2024: 7 · 2023: 14 · 2022: 20 · 2021: 9 · 2020: 16 · 2019: 9 · 2018: 8 · 2017: 11 · 2016: 5
FWCI
5.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
Funders
  • American Federation for Aging Research
  • Larry L. Hillblom Foundation (2009-A-001-CTR)
  • National Institutes of Health (AG009909)
  • U.S. Public Health Service (P01 041122)
  • National Institute on Aging (R01AG038688, F32AG043252, R37AG009909, P01AG041122, R37AG013925)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
simvastatin, cellular senescence, senescence-associated secretory phenotype, breast cancer, protein prenylation, geranylgeranyltransferase, Rac1, Cdc42, Rho GTPases, IL-6 secretion, senescence-associated inflammation, endocrine therapy resistance, senescent fibroblasts, statins, tumor cell proliferation
MeSH terms
Breast Neoplasms, Cell Survival, Fibroblasts, Humans, Protein Processing, Post-Translational, Cellular Senescence, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein, MAP Kinase Signaling System, Cell Line, Tumor, Cell Proliferation

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