Furin-instructed molecular self-assembly actuates endoplasmic reticulum stress-mediated apoptosis for cancer therapy

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Protein quality control and proteostasis are vital for cell survival, preventing endoplasmic reticulum (ER) stress and apoptosis.
• Dysfunctional proteostasis contributes to neurodegenerative diseases and presents a potential target for cancer therapy.

Purpose of the Study:

• To design a small molecule, 1-Nap, that utilizes furin-instructed self-assembly to selectively inhibit cancer cell growth.
• To investigate the mechanism by which 1-Nap induces ER stress and apoptosis in cancer cells.

Main Methods:

• Transmission electron microscopy (TEM) and HPLC tracing to analyze 1-Nap self-assembly.
• Fluorescence imaging and Western-blot analysis to assess ER stress and apoptosis.
• In vitro and in vivo studies on MDA-MB-468 cancer cells.

Main Results:

• 1-Nap undergoes furin-instructed cleavage, transforming from nanoparticles to nanofibers.
• The self-assembly of 1-Nap, not its ER targeting, is crucial for inducing ER stress and apoptosis.
• 1-Nap self-assembly impacts both ER and trans-Golgi network, potentially blocking ER-to-Golgi traffic.

Conclusions:

• Furin-instructed molecular self-assembly of 1-Nap selectively inhibits cancer cell growth by inducing ER stress and apoptosis.
• Blocking ER-to-Golgi traffic via molecular self-assembly is a potential mechanism for controlling cell fate.
• This approach offers a novel strategy for targeted proteostasis disturbance in cancer therapeutics.