Asteltoxin inhibits extracellular vesicle production through AMPK/mTOR-mediated activation of lysosome function

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Cancer cells release substantial extracellular vesicles (EVs), including exosomes, which are implicated in tumor progression.
• Targeting EV secretion presents a potential therapeutic strategy for cancer treatment.

Purpose of the Study:

• To identify novel inhibitors of extracellular vesicle (EV) secretion from a fungal natural product library.
• To investigate the mechanism of action of identified EV inhibitors.

Main Methods:

• Screening of a fungal natural product library using engineered cancer cells secreting luciferase-labeled EVs.
• Assessing the effect of asteltoxin on EV secretion, cellular ATP levels, mitochondrial function, and lysosome biogenesis.
• Utilizing electron microscopy to analyze multivesicular bodies (MVBs) and lysosomes.

Main Results:

• Asteltoxin was identified as an inhibitor of EV secretion, acting by inhibiting mitochondrial ATP synthase.
• Low concentrations of asteltoxin reduced EV secretion without inducing mitochondrial damage, by attenuating ATP levels and inactivating mTORC1.
• Asteltoxin treatment led to nuclear translocation of MiT/TFE, increased lysosome biogenesis, and decreased MVBs and EV levels.

Conclusions:

• Asteltoxin represents a new class of EV inhibitors that modulate the fate of multivesicular bodies (MVBs).
• The findings suggest a mechanism where asteltoxin-induced mTORC1 inactivation promotes lysosome activation, impacting MVB processing and EV release.