Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

Aging Cell. 2020 Mar;19(3):e13117. doi: 10.1111/acel.13117. Epub 2020 Feb 16.

Abstract

The accumulation of senescent cells (SnCs) is a causal factor of various age-related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin-proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases.

Keywords: MDM2; Senescence; USP7; apoptosis; p53; senolytics.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cellular Senescence / drug effects*
  • Cellular Senescence / genetics*
  • Doxorubicin / pharmacology
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Mice
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • RNA Interference
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Thiophenes / pharmacology
  • Transfection
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin-Specific Peptidase 7 / antagonists & inhibitors
  • Ubiquitin-Specific Peptidase 7 / genetics
  • Ubiquitin-Specific Peptidase 7 / metabolism*
  • Ubiquitination / drug effects
  • Ubiquitination / genetics

Substances

  • 1-(5-((2,4-difluorophenyl)thio)-4-nitrothiophen-2-yl)ethanone
  • P5091
  • TP53 protein, human
  • Thiophenes
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Doxorubicin
  • MDM2 protein, human
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • USP7 protein, human
  • Ubiquitin-Specific Peptidase 7
  • Usp7 protein, mouse