Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype

Christopher D Wiley,Fatouma Alimirah,Arturo V Orjalo,Jose Alberto Lopez-Dominguez,Christopher Benz,Pierre-Yves Desprez,Judith Campisi,Albert R Davalos,Gary Scott,Nicholas Schaum

doi:10.1038/s41598-018-20000-4

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.

Highlights

Cancer poses a major challenge to the longevity of mammals, and age is the largest risk factor for developing this disease[1]
Along with the permanent cell cycle arrest induced by the p53 and p16INK4a tumor suppressors[9,10,11], an important feature of senescent cells is the secretion of a myriad of biologically active factors, termed the senescence-associated secretory phenotype (SASP)[12]
A previous report showed that MDM2-p53 interaction antagonists can cause cancer cells to undergo apoptosis[36], a process to which senescent cells are resistant[37]

Summary

Introduction

Cancer poses a major challenge to the longevity of mammals, and age is the largest risk factor for developing this disease[1]. Along with the permanent cell cycle arrest induced by the p53 and p16INK4a tumor suppressors[9,10,11], an important feature of senescent cells is the secretion of a myriad of biologically active factors, termed the senescence-associated secretory phenotype (SASP)[12]. Because senescent cells increase with age[17,18,19] and are frequently found within hyperplastic and degenerative tissues[20,21], the SASP may be a major cause of inflammaging[22,23,24,25]. Compounds that modulate the SASP hold promise for ameliorating a number of diseases of aging, including cancer. In cancer cells, nutlin-3a inhibits the activity of NF-κB, a potent transcriptional www.nature.com/scientificreports/. The clinical importance of small-molecule MDM2 inhibitors like nutlin-3a spurred the discovery of similar compounds, such as MI-63, which are more efficient inhibitors of the MDM2-p53 interaction[30]

Methods

Results

Conclusion