Plasminogen activator inhibitor 1—insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence
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Cellular senescence is widely believed to play a key role in tumor suppression, but the molecular pathways that regulate senescence are only incompletely understood. By using a secretome proteomics approach, we identified insulin-like growth factor binding protein 3 (IGFBP3) as a secreted mediator of breast cancer senescence upon chemotherapeutic drug treatment. The senescence-inducing activity of IGFBP3 is inhibited by tissue-type plasminogen activator-mediated proteolysis, which is counteracted by plasminogen activator inhibitor 1 (PAI-1), another secreted mediator of senescence. We demonstrate that IGFBP3 is a critical downstream target of PAI-1-induced senescence. These results suggest a role for an extracellular cascade of secreted proteins in the regulation of cellular senescence.
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IGFBP3 is a SASP component that may help propagate senescence signals to neighboring cells.
“Other related factors, such as IGFBP3, have been implicated as SASP components that may play a role in the propagation of senescence signals to neighboring cells (42).”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [42]
PAI-1 can stabilize IGFBP3 by inhibiting tissue plasminogen activator, which normally cleaves IGFBP3.
“For example, PAI-1, a SASP factor produced by many cell types, can stabilize IGFBP3 by inhibition of tissue plasminogen activator, which normally cleaves it.”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [42]
Ability of IGFBP3 to induce senescence is regulated by PAI-1 system.
“The ability of IGFBP3 to induce senescence is regulated by tissue-type plasminogen activator inhibitor-1 (PAI-1) system (Elzi et al., 2012).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Elzi et al., 2012
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- Authors
- Elzi, D. J., Lai, Y., Song, M., Hakala, K., Weintraub, S. T., & Shiio, Y.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-07-09
- Volume
- 109
- Issue
- 30
- Pages
- 12052-12057
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3409757
- OpenAlex
- W2074103997
- Cited by
- 154
- References
- 34
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 17 · 2023: 11 · 2022: 11 · 2021: 11 · 2020: 11 · 2019: 11 · 2018: 10 · 2017: 13 · 2016: 15 · 2015: 13 · 2014: 8 · 2013: 5
- FWCI
- 5.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA054174)
- University of Texas Health Science Center at San Antonio
- National Institute on Aging (R21AG029587, AG029587)
- National Cancer Institute (CA-054174, P30CA054174, R01CA125020, CA125020, CA137568, R21CA137568)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- cellular senescence, insulin-like growth factor binding protein-3, plasminogen activator inhibitor-1, tissue plasminogen activator, breast cancer, chemotherapy-induced senescence, secretome, tumor suppression, proteolysis
- MeSH terms
- Analysis of Variance, beta-Galactosidase, Culture Media, Doxorubicin, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Neoplasms, Tissue Plasminogen Activator, Stress, Physiological, Tumor Cells, Cultured, Immunoblotting, Cellular Senescence, Plasminogen Activator Inhibitor 1, DNA Primers, Insulin-Like Growth Factor Binding Protein 3, Reverse Transcriptase Polymerase Chain Reaction, RNA, Small Interfering, Proteomics, Cell Line, Tumor, Proteolysis
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