Format

Send to

Choose Destination
Life Sci Alliance. 2019 Jun 26;2(3). pii: e201900439. doi: 10.26508/lsa.201900439. Print 2019 Jun.

Tamoxifen blocks retrograde trafficking of Shiga toxin 1 and 2 and protects against lethal toxicosis.

Author information

1
Division of Pharmacology and Toxicology, College of Pharmacy; Institute for Cellular and Molecular Biology; and Institute for Neuroscience, The University of Texas at Austin, Austin, TX, USA.
2
Center for Innovative Drug Discovery, Department of Chemistry, University of Texas San Antonio, San Antonio, TX, USA.
3
Division of Pharmacology and Toxicology, College of Pharmacy; Institute for Cellular and Molecular Biology; and Institute for Neuroscience, The University of Texas at Austin, Austin, TX, USA som@austin.utexas.edu.

Abstract

Shiga toxin 1 (STx1) and 2 (STx2), produced by Shiga toxin-producing Escherichia coli, cause lethal untreatable disease. The toxins invade cells via retrograde trafficking. Direct early endosome-to-Golgi transport allows the toxins to evade degradative late endosomes. Blocking toxin trafficking, particularly at the early endosome-to-Golgi step, is appealing, but transport mechanisms of the more disease-relevant STx2 are unclear. Using data from a genome-wide siRNA screen, we discovered that disruption of the fusion of late endosomes, but not autophagosomes, with lysosomes blocked the early endosome-to-Golgi transport of STx2. A subsequent screen of clinically approved lysosome-targeting drugs identified tamoxifen (TAM) to be a potent inhibitor of the trafficking and toxicity of STx1 and STx2 in cells. The protective effect was independent of estrogen receptors but dependent on the weak base property of TAM, which allowed TAM to increase endolysosomal pH and alter endosomal dynamics. Importantly, TAM treatment enhanced survival of mice injected with a lethal dose of STx1 or STx2. Thus, it may be possible to repurpose TAM for treating Shiga toxin-producing E. coli infections.

PMID:
31243048
PMCID:
PMC6599968
DOI:
10.26508/lsa.201900439
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center