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Furin-Instructed Molecular Self-Assembly Actuates Endoplasmic Reticulum Stress-Mediated Apoptosis for Cancer Therapy

Abstract

The protein quality control and proteostasis are essential to maintain cell survival, once disordered, will trigger endoplasmic reticulum (ER) stress and even initiate apoptosis. Severe ER stress-mediated apoptosis is not only the cause of neurodegenerative diseases but also expected to be a new target for cancer therapy. In this study, we designed a small molecule of 1-Nap to execute furin-instructed molecular self-assembly for selectively inhibiting the growth of MDA-MB-468 cells in vitro and in vivo. According to transmission electron microscopy (TEM) and HPLC tracing analysis, 1-Nap is capable of self-assembly under the cleavage of furin to transform from nanoparticles to nanofibers. Fluorescent imaging and Western-blot indicate that the furin-instructed self-assembly of 1-Nap rather than its ER-targeting interaction is indispensable for the ER stress and activating apoptosis. The furin-instructed self-assembly of 1-Nap associates with both the ER and the trans-Golgi network (1-Nap’s ER targeting and furin’s location), which inspires us to reasonably believe the blocking of ER-to-Golgi traffic in the secretory pathway by molecular self-assembly may be the intrinsic motivation for controlling cell fate. This work provides a new way to targeted disturb the proteostasis of cells through molecular self-assembly for developing cancer therapeutics.

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Supplementary files

Article information


Submitted
07 Jan 2020
Accepted
18 May 2020
First published
19 May 2020

Nanoscale, 2020, Accepted Manuscript
Article type
Paper

Furin-Instructed Molecular Self-Assembly Actuates Endoplasmic Reticulum Stress-Mediated Apoptosis for Cancer Therapy

C. Fu, J. Zhan, J. Huai, S. Ma, M. Li, G. Chen, M. Chen, Y. Cai and C. Ou, Nanoscale, 2020, Accepted Manuscript , DOI: 10.1039/D0NR00151A

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