An Enzyme-Catalyzed Polymerization Strategy Disrupts Protein Homeostasis for Improved Tumor Therapy

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Proteins are vital for cellular function and homeostasis.
• Dysregulated protein homeostasis (proteostasis) is linked to cancer development and progression.
• Targeting proteostasis in tumor cells offers a promising therapeutic avenue for cancer treatment.

Purpose of the Study:

• To develop an enzyme-catalyzed polymerization strategy to disrupt tumor proteostasis.
• To induce specific overaccumulation of misfolded proteins in melanoma cells.
• To explore a novel therapeutic approach for cancer therapy by targeting protein homeostasis.

Main Methods:

• Utilized a tyrosinase-catalyzed peptide fragment for polymerization.
• Conjugated the peptide to bortezomib via a pH-responsive phenylboronate linkage for controlled release in acidic tumor lysosomes.
• Leveraged tyrosine-catalyzed polymerization to covalently bind proteins and generate misfolded protein aggregates.
• Inhibited proteasome activity with bortezomib to enhance misfolded protein accumulation.

Main Results:

• The strategy successfully induced overaccumulation of misfolded proteins in melanoma cells.
• The pH-responsive linkage ensured controlled release of bortezomib within tumor cells.
• Tyrosine-catalyzed polymerization led to the formation of excess misfolded proteins.
• The combined effect triggered endoplasmic reticulum stress and activated apoptotic pathways.

Conclusions:

• Disrupting proteostasis by inducing misfolded protein overaccumulation is a viable cancer therapy strategy.
• The developed enzyme-catalyzed polymerization system offers targeted disruption of tumor protein homeostasis.
• This approach provides a novel method for specifically regulating misfolded protein levels in cancer cells for therapeutic benefit.