RT Journal Article
SR Electronic
T1 Peptide inhibitors targeting FOXO4-p53 interactions and inducing senescent cancer cell-specific apoptosis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.09.04.610228
DO 10.1101/2024.09.04.610228
A1 Kang, Donghoon
A1 Lim, Yeji
A1 Ahn, Dabin
A1 Lee, Jaeseok
A1 Park, Chin-Ju
YR 2024
UL http://biorxiv.org/content/early/2024/09/04/2024.09.04.610228.abstract
AB Cellular senescence, marked by irreversible cell cycle arrest and the secretion of proinflammatory factors, contributes to aging and cancer recurrence. Chemotherapy can also induce senescence; senescent cells often resist apoptosis and promote tumor recurrence. The interaction between FOXO4 and p53 sustains cell survival. Herein, we used biophysical techniques and conducted cellular experiments to develop a peptide inhibitor targeting this interaction to eliminate senescent cancer cells. We identified key regions in the p53 transactivation domain (TAD) involved in FOXO4 binding and designed an optimized peptide inhibitor (CPP-CAND) with improved cell permeability. CPP-CAND showed high selectivity and potency in inducing apoptosis in senescent cells by disrupting FOXO4-p53 foci and activating caspase pathways. It is effective against senescent cancer cells induced by doxorubicin and cisplatin, highlighting its potential as a senolytic drug. Thus, CPP-CAND is a promising therapeutic candidate with improved selectivity, efficacy, and cost-effectiveness.Competing Interest StatementThe authors have declared no competing interest.