Targeting the MDM2-MDM4 interaction interface reveals an otherwise therapeutically active wild-type p53 in colorectal cancer.

ABSTRACT: Targeting the heterodimer MDM2/MDM4 is a novel and effective route for the reactivation of wild-type p53 in human tumors with reduced toxicity in nontransformed cells. To improve the therapeutic potential of peptides that interfere with MDM4 binding to MDM2, we demonstrated the tumor-suppressive activity of a short peptide (Pep3S), which is composed of the last five amino acids of the MDM4 protein. Compared to longer peptides (previously identified), Pep3S binds MDM2 with high affinity, increases p53-dependent cell death in 2D and 3D colorectal cancer models, and is more efficacious in suppressing xenograft tumor growth. Furthermore, its encapsulation in poly (lactic-co-glycolic acid) (PLGA) nanoparticles potentiated and prolonged its activity. A p53-specific target gene array revealed an

SUBMITTER: Valentini S 

PROVIDER: S-EPMC12330940 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature