Metformin reveals a mitochondrial copper addiction of mesenchymal cancer cells

Area of Science:

• Biochemistry
• Cancer Biology
• Mitochondrial Medicine

Background:

• Metformin, a common drug, selectively eliminates persister cancer cells via unknown mechanisms.
• Persister cancer cells evade therapy, contributing to treatment failure and relapse.

Purpose of the Study:

• To elucidate the precise mechanisms by which metformin targets persister cancer cells.
• To develop a tool for visualizing metformin's action within cancer cells.
• To investigate the role of mitochondrial copper in cancer cell maintenance and transition.

Main Methods:

• Development of a click chemistry-labelable metformin surrogate.
• Utilizing fluorescence microscopy and cyclic voltammetry for mechanistic studies.
• Employing various cancer cell models to assess drug potency and effects.

Main Results:

• The metformin surrogate demonstrated higher potency than metformin in tested cancer models.
• Visual evidence confirmed mitochondrial targeting by this drug class.
• Metformin was shown to target mitochondrial copper, inducing reactive oxygen species, mitochondrial dysfunction, and apoptosis.
• Mitochondrial copper is essential for maintaining the mesenchymal state in human cancer cells.
• Metformin blocks the epithelial-to-mesenchymal transition, a key process in persister cell formation.

Conclusions:

• Metformin's anti-cancer activity involves direct targeting of mitochondrial copper.
• This targeting disrupts mitochondrial function and induces cancer cell death.
• Metformin inhibits the epithelial-to-mesenchymal transition, crucial for preventing persister cell generation.