Chaperone-targeting cytotoxin and endoplasmic reticulum stress-inducing drug synergize to kill cancer cells

Abstract

Diverse physiological and therapeutic insults that increase the amount of unfolded or misfolded proteins in the ER induce the unfolded protein response, an evolutionarily conserved protective mechanism that manages ER stress. GRP78/BiP is an ER-resident protein that plays a central role in the ER stress response and is the only known substrate of the proteolytic A subunit (SubA) of a novel bacterial AB5 toxin. Here we report that an engineered fusion protein, EGF-SubA, combining EGF and SubA is highly toxic to growing and confluent EGFR-expressing cancer cells, and its cytotoxicity is mediated by a remarkably rapid cleavage of GRP78/BiP. Systemic delivery of EGF-SubA results in a significant inhibition of human breast and prostate tumor xenografts in mouse models. Furthermore, EGF-SubA dramatically increases the sensitivity of cancer cells to the ER stress-inducing drug thapsigargin, and vice-versa, demonstrating the first example of mechanism-based synergism in the action of a cytotoxin and an ER-targeting drug