Uncoupling the Senescence-Associated Secretory Phenotype from Cell Cycle Exit via Interleukin-1 Inactivation Unveils Its Protumorigenic Role
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Cellular senescence has emerged as a potent tumor suppressor mechanism in numerous human neoplasias. Senescent cells secrete a distinct set of factors, collectively termed the senescence-associated secretory phenotype (SASP), which has been postulated to carry both pro- and antitumorigenic properties depending on tissue context. However, the in vivo effect of the SASP is poorly understood due to the difficulty of studying the SASP independently of other senescence-associated phenotypes. Here, we report that disruption of the interleukin-1 (IL-1) pathway completely uncouples the SASP from other senescence-associated phenotypes such as cell cycle exit. Transcriptome profiling of IL-1 receptor (IL-1R)-depleted senescent cells indicates that IL-1 controls the late arm of the senescence secretome, which consists of proinflammatory cytokines induced by NF-κB. Our data suggest that both IL-1α and IL-1β signal through IL-1R to upregulate the SASP in a cooperative manner. Finally, we show that IL-1α inactivation impairs tumor progression and immune cell infiltration without affecting cell cycle arrest in a mouse model of pancreatic cancer, highlighting the protumorigenic property of the IL-1-dependent SASP in this context. These findings provide novel insight into the therapeutic potential of targeting the IL-1 pathway in inflammatory cancers.
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Through SASP, senescent cells contribute to cancer development, metastasis, treatment failure and increased recurrence risk.
“In addition, through SASP, senescent cells contribute to cancer development162,163 and metastasis164, treatment failure and increased risk of recurrence165.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [164]
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- Authors
- Lau, L., Porciuncula, A., Yu, A., Iwakura, Y., & David, G.
- Affiliations
- New York University (US)
- Tokyo University of Science (JP)
- Corresponding author
- David, Gregory
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2019-06-01
- Volume
- 39
- Issue
- 12
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC6549465
- OpenAlex
- W2937053683
- Cited by
- 119
- References
- 62
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 22 · 2023: 20 · 2022: 18 · 2021: 23 · 2020: 9 · 2019: 4
- FWCI
- 9.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (R01CA148639, R21CA206013, R21CA155736, F31CA206387)
- Samuel Waxman Cancer Research Foundation
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- cellular senescence, senescence-associated secretory phenotype, interleukin-1, interleukin-1 receptor, IL-1α, IL-1β, NF-κB, inflammatory cytokines, cell cycle exit, pancreatic cancer, tumor immune cell infiltration
- MeSH terms
- Animals, Cell Cycle, Humans, Interleukin-1, Neoplasm Transplantation, Pancreatic Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Cytokines, NF-kappa B, Cellular Senescence, Receptors, Interleukin-1, Gene Expression Profiling, Cell Line, Tumor, Mice, HEK293 Cells
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