Glutathionylation-dependent proteasomal degradation of wide-spectrum mutant p53 proteins by engineered zeolitic...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Biology

Background:

• Point mutations in the TP53 gene are common in human cancers, producing stabilized mutant p53 proteins (mutp53) that promote tumor growth.
• Targeting mutp53 for degradation is a potential cancer therapy, but current small-molecule inducers are insufficient.

Purpose of the Study:

• To investigate the potential of pH-responsive zeolitic imidazolate framework-8 (ZIF-8) as a novel therapeutic agent for inducing mutp53 degradation.
• To evaluate the efficacy of ZIF-8 in degrading various mutp53 proteins and its therapeutic potential in preclinical cancer models.

Main Methods:

• Utilized pH-responsive ZIF-8 nanoparticles for intracellular delivery.
• Investigated ZIF-8-induced degradation pathways, including ubiquitination and glutathionylation.
• Assessed ZIF-8 efficacy in cancer cell lines and in vivo models, including ovarian and breast cancer xenografts.

Main Results:

• ZIF-8 effectively induced ubiquitination-mediated and glutathionylation-dependent proteasomal degradation of nine tested mutp53 proteins, sparing wild-type p53.
• Internalized ZIF-8 decomposed in acidic endosomes, increasing intracellular Zn++ levels and decreasing the GSH:GSSG ratio, essential for mutp53 degradation.
• ZIF-8 modified with Z1-RGD peptide showed enhanced cellular uptake and preferentially killed mutp53-expressing cancer cells, demonstrating significant therapeutic efficacy in ovarian and breast cancer models.

Conclusions:

• pH-responsive ZIF-8 is a novel and effective nanomaterial for inducing broad-spectrum mutp53 degradation.
• Engineered nanomaterials like ZIF-8 represent a promising alternative to small molecules for developing targeted therapies against p53-mutated cancers.