Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL

Nat Commun. 2016 Apr 6;7:11190. doi: 10.1038/ncomms11190.

Abstract

Senescent cells, formed in response to physiological and oncogenic stresses, facilitate protection from tumourigenesis and aid in tissue repair. However, accumulation of such cells in tissues contributes to age-related pathologies. Resistance of senescent cells to apoptotic stimuli may contribute to their accumulation, yet the molecular mechanisms allowing their prolonged viability are poorly characterized. Here we show that senescent cells upregulate the anti-apoptotic proteins BCL-W and BCL-XL. Joint inhibition of BCL-W and BCL-XL by siRNAs or the small-molecule ABT-737 specifically induces apoptosis in senescent cells. Notably, treatment of mice with ABT-737 efficiently eliminates senescent cells induced by DNA damage in the lungs as well as senescent cells formed in the epidermis by activation of p53 through transgenic p14(ARF). Elimination of senescent cells from the epidermis leads to an increase in hair-follicle stem cell proliferation. The finding that senescent cells can be eliminated pharmacologically paves the way to new strategies for the treatment of age-related pathologies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Biphenyl Compounds / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects
  • DNA Damage
  • Epidermis / drug effects
  • Epidermis / metabolism
  • Epidermis / pathology
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation
  • Humans
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nitrophenols / pharmacology*
  • Piperazines / pharmacology
  • Primary Cell Culture
  • Proteins / antagonists & inhibitors*
  • Proteins / genetics
  • Proteins / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Sulfonamides / pharmacology*
  • Tumor Suppressor Protein p14ARF / genetics
  • Tumor Suppressor Protein p14ARF / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • bcl-X Protein / antagonists & inhibitors*
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • ABT-737
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Bcl2l1 protein, mouse
  • Bcl2l2 protein, mouse
  • Biphenyl Compounds
  • Nitrophenols
  • Piperazines
  • Proteins
  • RNA, Small Interfering
  • Sulfonamides
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • bcl-X Protein