Enzymatic Assemblies Disrupt the Membrane and Target Endoplasmic Reticulum for Selective Cancer Cell Death

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Therapeutics

Background:

• The endoplasmic reticulum (ER) plays crucial roles in protein synthesis, folding, and calcium homeostasis.
• The ER is an emerging target for cancer therapy, but selective targeting strategies are limited.
• Disrupting cancer cell membranes is a potential therapeutic approach.

Purpose of the Study:

• To develop novel peptide assemblies for selective cancer cell targeting.
• To investigate the mechanism of peptide assemblies in inducing cancer cell death.
• To explore the potential of targeting the endoplasmic reticulum for cancer treatment.

Main Methods:

• Enzymatic generation of crescent-shaped supramolecular peptide assemblies.
• Sedimentation assays and live cell imaging to assess membrane interaction and integrity.
• Transmission electron microscopy (TEM), static light scattering (SLS), and critical micelle concentration (CMC) for structural analysis.
• Fluorescent imaging, Western blot, and ELISA to evaluate ER accumulation, ER stress, and caspase activation.

Main Results:

• Crescent-shaped peptide assemblies were successfully synthesized and shown to interact with lipid membranes.
• These assemblies impair cell membrane integrity and lead to cell death.
• The assemblies accumulate on the endoplasmic reticulum, inducing ER stress and activating caspase-dependent cell death pathways.
• The crescent-shaped morphology is critical for membrane interaction and cell fate determination.

Conclusions:

• Enzymatically generated crescent-shaped peptide assemblies effectively disrupt cancer cell membranes and selectively target the ER.
• This approach induces cancer cell death via ER stress and caspase activation.
• These peptide assemblies represent a promising new strategy for developing novel ER-targeted anticancer therapeutics.