PT  - JOURNAL ARTICLE
AU  - Kang, Donghoon
AU  - Lim, Yeji
AU  - Ahn, Dabin
AU  - Lee, Jaeseok
AU  - Park, Chin-Ju
TI  - Peptide inhibitors targeting FOXO4-p53 interactions and inducing senescent cancer cell-specific apoptosis
AID  - 10.1101/2024.09.04.610228
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2024.09.04.610228
4099  - http://biorxiv.org/content/early/2024/09/04/2024.09.04.610228.short
4100  - http://biorxiv.org/content/early/2024/09/04/2024.09.04.610228.full
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.