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Synergistic chemical combination for cell cycle restoration in senescent cells via FoxM1 and E2F1 activation

ABSTRACT: Cellular senescence wreaks defects in the aging organism. In this study, we co-treated two chemicals: rho-associated protein kinase (ROCK) inhibitor (Y-27632) and ataxia telangiectasia mutated (ATM) inhibitor (KU-60019) to overcome senescence more efficaciously, these two chemicals are already revealed to have senomorphic effects, suppressing senescent phenotypes. We find out that cocktail treatment synergistically alleviates diverse senescent phenotypes in senescent human dermal fibroblast cells. Through transcriptomic approach, FOXM1 and E2F1 are identified as key transcription factor of synergism to normalize senescent cells, of which activities are attenuated by senescence both in vitro and in vivo, but revitalized by co-treatment. Activation of FOXM1 precedes activation of E2F1 and mediates transcription of numerous genes totally shut off by cellular senescence, including E2F1. After that, E2F1 participates in transcriptomic change. For that, Cyclin-dependent kinase (CDKs), where are the confluences of both ATM-Chk2-CDKs and ROCK-Akt-CDKs signaling axes, are direct regulators of these transcription factors. Surprisingly, canonical aging-related CDK inhibitors have nothing to do with the onset of senomorphism. As the order of activations of FOXM1 and E2F1 that are in charge of G2 and G1 phase transition respectively, chemical combination releases senescent cell arrest in order of G2 then G1. Altogether, our data provide new insight into the way of amelioration of aging via pivotal cell cycle transcription factors, FOXM1 and E2F1, which are synergistically stimulated by inhibiting senescence-associated kinases, ATM and ROCK.

ORGANISM(S): Homo sapiens

PROVIDER: GSE178115 | GEO | 2022/06/22

REPOSITORIES: GEO

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