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Uncoupling the Senescence-Associated Secretory Phenotype from Cell Cycle Exit via Interleukin-1 Inactivation Unveils Its Protumorigenic Role.

Authors
  • Lau, Lena1
  • Porciuncula, Angelo1
  • Yu, Alex1
  • Iwakura, Yoichiro2
  • David, Gregory3, 4, 5
  • 1 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
  • 2 Research Institute for Biomedical Sciences, Tokyo University of Science, Yamazaki, Noda, Japan. , (Japan)
  • 3 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA [email protected]
  • 4 Deparment of Urology, New York University School of Medicine, New York, New York, USA.
  • 5 NYU Cancer Institute, New York University School of Medicine, New York, New York, USA.
Type
Published Article
Journal
Molecular and Cellular Biology
Publisher
American Society for Microbiology
Publication Date
Jun 15, 2019
Volume
39
Issue
12
Identifiers
DOI: 10.1128/MCB.00586-18
PMID: 30988157
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2019 American Society for Microbiology.

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