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Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype.

  • Author(s): Wiley, Christopher D
  • Schaum, Nicholas
  • Alimirah, Fatouma
  • Lopez-Dominguez, Jose Alberto
  • Orjalo, Arturo V
  • Scott, Gary
  • Desprez, Pierre-Yves
  • Benz, Christopher
  • Davalos, Albert R
  • Campisi, Judith
  • et al.
Abstract

Processes that have been linked to aging and cancer include an inflammatory milieu driven by senescent cells. Senescent cells lose the ability to divide, essentially irreversibly, and secrete numerous proteases, cytokines and growth factors, termed the senescence-associated secretory phenotype (SASP). Senescent cells that lack p53 tumor suppressor function show an exaggerated SASP, suggesting the SASP is negatively controlled by p53. Here, we show that increased p53 activity caused by small molecule inhibitors of MDM2, which promotes p53 degradation, reduces inflammatory cytokine production by senescent cells. Upon treatment with the MDM2 inhibitors nutlin-3a or MI-63, human cells acquired a senescence-like growth arrest, but the arrest was reversible. Importantly, the inhibitors reduced expression of the signature SASP factors IL-6 and IL-1α by cells made senescent by genotoxic stimuli, and suppressed the ability of senescent fibroblasts to stimulate breast cancer cell aggressiveness. Our findings suggest that MDM2 inhibitors could reduce cancer progression in part by reducing the pro-inflammatory environment created by senescent cells.

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