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

Mol Cell Biol. 2019 May 28;39(12):e00586-18. doi: 10.1128/MCB.00586-18. Print 2019 Jun 15.

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.

Keywords: cancer; inflammation; interleukin-1; senescence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Line, Tumor
  • Cellular Senescence
  • Cytokines / genetics*
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Interleukin-1 / metabolism*
  • Mice
  • NF-kappa B / pharmacology
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / immunology
  • Receptors, Interleukin-1 / genetics*
  • Signal Transduction

Substances

  • Cytokines
  • Interleukin-1
  • NF-kappa B
  • Receptors, Interleukin-1