High content screening identifies monensin as an EMT-selective cytotoxic compound

Area of Science:

• Oncology
• Cell Biology
• Pharmacology

Background:

• Epithelial-to-mesenchymal transition (EMT) is a key process in cancer metastasis and drug resistance.
• Targeting cancer cells in an EMT-like state presents a potential therapeutic avenue.

Purpose of the Study:

• To develop a high-content screening protocol to identify compounds selectively targeting EMT-like cancer cells.
• To evaluate the mechanism of action of identified compounds, particularly monensin.

Main Methods:

• A cell imaging-based high-content screen of 2,640 compounds was performed.
• Monensin's effects on apoptosis, cell cycle, reactive oxygen species (ROS), Golgi apparatus, and mitochondrial function were assessed.
• Monensin's toxicity was evaluated across 24 human cancer cell lines, with sensitivity classified by IC50 values.

Main Results:

• Salinomycin and monensin demonstrated potent and selective cytotoxicity against EMT-like cells.
• Monensin (10 nM) induced apoptosis, cell cycle arrest, increased ROS, Golgi swelling, and mitochondrial dysfunction in TEM 4-18 cells.
• EMT was the top enriched gene set in monensin-sensitive cell lines, which also showed increased 3H-monensin uptake.

Conclusions:

• Monensin exhibits selective cytotoxicity against EMT-like cancer cells at nanomolar concentrations.
• This selectivity is linked to EMT status and enhanced monensin uptake.
• Monensin represents a promising therapeutic candidate for targeting metastatic and drug-resistant cancers.