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Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype.
- Source :
-
Scientific reports [Sci Rep] 2018 Feb 05; Vol. 8 (1), pp. 2410. Date of Electronic Publication: 2018 Feb 05. - Publication Year :
- 2018
-
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.
- Subjects :
- Cell Cycle Checkpoints drug effects
Cell Cycle Checkpoints genetics
Cell Line
Cellular Senescence genetics
Cellular Senescence radiation effects
Epithelial Cells cytology
Epithelial Cells drug effects
Epithelial Cells metabolism
Epithelial Cells radiation effects
Fibroblasts cytology
Fibroblasts drug effects
Fibroblasts metabolism
Fibroblasts radiation effects
Foreskin cytology
Gamma Rays
Humans
Interleukin-1alpha antagonists & inhibitors
Interleukin-1alpha genetics
Interleukin-1alpha metabolism
Interleukin-6 antagonists & inhibitors
Interleukin-6 genetics
Interleukin-6 metabolism
Lung cytology
Male
Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors
Proto-Oncogene Proteins c-mdm2 metabolism
Tumor Suppressor Protein p53 agonists
Tumor Suppressor Protein p53 metabolism
Cellular Senescence drug effects
Enzyme Inhibitors pharmacology
Imidazoles pharmacology
Indoles pharmacology
Piperazines pharmacology
Proto-Oncogene Proteins c-mdm2 genetics
Spiro Compounds pharmacology
Tumor Suppressor Protein p53 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 29402901
- Full Text :
- https://doi.org/10.1038/s41598-018-20000-4