The antibiotic drug trimethoprim suppresses tumour growth and metastasis via targeting Snail.

Abstract

BACKGROUND AND PURPOSE:

The zinc finger transcription factor Snail is aberrantly activated in many human cancers and strongly associated with poor prognosis. As a transcription factor, Snail has been traditionally considered an 'undruggable' target. Here, we identified a potent small-molecule inhibitor of Snail, namely trimethoprim, and investigated its potential antitumour effects and the underlying mechanisms.

EXPERIMENTAL APPROACH:

The inhibitory action of trimethoprim on Snail protein and the related molecular mechanisms were revealed by molecular docking, biolayer interferometry, immunoblotting, immunoprecipitation, qRT-PCR, pull-down and cycloheximide pulse-chase assays. The anti-proliferative and anti-metastatic effects of trimethoprim via targeting Snail were tested in multiple cell-based assays and animal models.

KEY RESULTS:

This study identified trimethoprim, an antimicrobial drug, as a potent antitumour agent via targeting Snail. Molecular modelling analysis predicted that trimethoprim directly binds to the arginine-174 pocket of Snail protein. We further discovered that trimethoprim strongly interrupts the interaction of Snail with CREB-binding protein (CBP)/p300, which consequently suppresses Snail acetylation and promotes Snail degradation through the ubiquitin-proteasome pathway. Furthermore, trimethoprim sufficiently inhibited the proliferation, epithelial-mesenchymal transition (EMT) and migration of cancer cells in vitro via specifically targeting Snail. More importantly, trimethoprim effectively reduced Snail-driven tumour growth and metastasis to vital organs such as lung, bone and liver.

CONCLUSIONS AND IMPLICATIONS:

These findings indicate, for the first time, that trimethoprim suppresses tumour growth and metastasis via targeting Snail. This study provides insights for a better understanding of the anticancer effects of trimethoprim and offers a potential anticancer therapeutic agent for clinical treatment.

• Authors: Bo-Xue Ren, Yang Li, Hong-Mei Li, Tao Lu, Zhao-Qiu Wu, Rong Fu
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 179 Issue 11 Pg. 2659-2677 (06 2022) ISSN: 1476-5381 [Electronic] England
• PMID: 34855201 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The British Pharmacological Society.

Chemical References

• Anti-Bacterial Agents
• Snail Family Transcription Factors
• Transcription Factors
• Trimethoprim

Topics

• Animals
• Anti-Bacterial Agents (pharmacology)
• Cell Line, Tumor
• Cell Movement
• Molecular Docking Simulation
• Neoplasm Metastasis
• Snail Family Transcription Factors (metabolism)
• Transcription Factors (metabolism)
• Trimethoprim (pharmacology)