Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function

Area of Science:

• Biochemistry
• Cell Biology
• Oncology

Background:

• Antioxidant vitamin E supplements are linked to increased prostate cancer (PC) risk in men.
• The protective effects of pro-oxidants against PC remain largely unexplored.

Purpose of the Study:

• To investigate the potential of pro-oxidant vitamin K precursor, menadione sodium bisulfite (MSB), in suppressing PC progression.
• To elucidate the mechanism of action of MSB in cancer cells and its therapeutic potential in other diseases.

Main Methods:

• Administration of MSB to mice with induced prostate cancer.
• Investigating the interaction of MSB with the class III phosphatidylinositol 3-kinase VPS34.
• Testing MSB in a mouse model of myotubular myopathy caused by MTM1 loss.

Main Results:

• MSB suppressed prostate cancer progression in mice, inducing oxidative cell death.
• MSB was found to antagonize VPS34 through oxidation of key cysteines, indicating a redox checkpoint in sorting.
• Dietary MSB improved muscle histology, function, and lifespan in the myotubular myopathy model.

Conclusions:

• Pro-oxidant MSB demonstrates therapeutic potential against prostate cancer and myotubular myopathy.
• The findings highlight a redox checkpoint in cellular sorting regulated by VPS34.
• Understanding pro-oxidant selectivity opens new avenues for therapeutic development.