C-Terminal p53 Palindromic Tetrapeptide Restores Full Apoptotic Function to Mutant p53 Cancer Cells In Vitro and In...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• A synthetic monomer peptide from p53 C-terminus induced apoptosis in mutant p53 cells but had a short half-life.
• Peptide instability was attributed to a random coil topology, limiting therapeutic potential.

Purpose of the Study:

• To develop a more stable peptide by mimicking the p53 tetramer structure.
• To evaluate the efficacy and specificity of the novel peptide in inducing apoptosis in cancer cells.

Main Methods:

• A 4 repeat-palindromic-p53 peptide (4R-Pal-p53p) was designed, incorporating p53 sequences and mimicking tetramer formation.
• The peptide's activity was tested exogenously using an Antennapedia carrier and endogenously via doxycycline induction.
• Apoptosis induction, gene expression, and toxicity in normal stem cells were assessed.

Main Results:

• The exogenous 4R-Pal-p53p-Ant peptide showed over five-fold greater potency than the monomeric peptide, inducing 75% cell death in cancer cells.
• Endogenous 4R-Pal-p53p expression resulted in 43% cell death, whereas monomeric peptide expression showed no significant effect.
• The peptide activated extrinsic and intrinsic apoptosis pathways, increased reactive oxygen species, and upregulated p53 target genes (Bax, Fas) without toxicity to normal stem cells.

Conclusions:

• The 4R-Pal-p53p peptide is a stable and potent inducer of apoptosis in mutant p53 cancer cells.
• This peptide restores the apoptotic potential of mutant p53 and exhibits specific targeting of malignant cells.
• The findings support the therapeutic potential of 4R-Pal-p53p for treating p53-mutated cancers.