Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-15719-6
Keywords
-
Categories
Funding
- Japan Agency of Medical Research and Development (AMED) [19gm5010001h0003, 19cm0106401h0004]
- Japan Society for the Promotion of Science (JSPS) [18K15065]
- Taniguchi Memorial Fellowship Program
- Grants-in-Aid for Scientific Research [18K15065] Funding Source: KAKEN
Ask authors/readers for more resources
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. Senescent cells can influence the tumour microenvironment by secreting immunomodulatory factors and are thus a therapeutic target. Here, the authors identify a compound that degrades BET leading to DNA damage and activation of autophagy and a reduction in tumour growth.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available