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Uncoupling the Senescence-Associated Secretory Phenotype from Cell Cycle Exit via Interleukin-1 Inactivation Unveils Its Protumorigenic Role.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2019 May 28; Vol. 39 (12). Date of Electronic Publication: 2019 May 28 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- 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.<br /> (Copyright © 2019 American Society for Microbiology.)
- Subjects :
- Animals
Cell Cycle
Cell Line, Tumor
Cellular Senescence
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Mice
NF-kappa B pharmacology
Neoplasm Transplantation
Pancreatic Neoplasms immunology
Signal Transduction
Cytokines genetics
Gene Expression Profiling methods
Interleukin-1 metabolism
Pancreatic Neoplasms genetics
Receptors, Interleukin-1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5549
- Volume :
- 39
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 30988157
- Full Text :
- https://doi.org/10.1128/MCB.00586-18