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A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells

Nature Communications, ISSN: 2041-1723, Vol: 11, Issue: 1, Page: 1935
2020
  • 131
    Citations
  • 0
    Usage
  • 189
    Captures
  • 1
    Mentions
  • 1
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    131
  • Captures
    189
  • Mentions
    1
    • Blog Mentions
      1
      • Blog
        1
  • Social Media
    1
    • Shares, Likes & Comments
      1
      • Facebook
        1

Article Description

Although cellular senescence acts primarily as a tumour suppression mechanism, the accumulation of senescent cells in vivo eventually exerts deleterious side effects through inflammatory/tumour-promoting factor secretion. Thus, the development of new drugs that cause the specific elimination of senescent cells, termed senolysis, is anticipated. Here, by an unbiased high-throughput screening of chemical compounds and a bio-functional analysis, we identify BET family protein degrader (BETd) as a promising senolytic drug. BETd provokes senolysis through two independent but integrated pathways; the attenuation of non-homologous end joining (NHEJ), and the up-regulation of autophagic gene expression. BETd treatment eliminates senescent hepatic stellate cells in obese mouse livers, accompanied by the reduction of liver cancer development. Furthermore, the elimination of chemotherapy-induced senescent cells by BETd increases the efficacy of chemotherapy against xenograft tumours in immunocompromised mice. These results reveal the vulnerability of senescent cells and open up possibilities for its control.

Bibliographic Details

Wakita, Masahiro; Takahashi, Akiko; Sano, Osamu; Loo, Tze Mun; Imai, Yoshinori; Narukawa, Megumi; Iwata, Hidehisa; Matsudaira, Tatsuyuki; Kawamoto, Shimpei; Ohtani, Naoko; Yoshimori, Tamotsu; Hara, Eiji

Springer Science and Business Media LLC

Chemistry; Biochemistry, Genetics and Molecular Biology; Physics and Astronomy

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