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

ABSTRACT: Cancer cells secrete aberrantly large amounts of extracellular vesicles (EVs) including exosomes, which originate from multivesicular bodies (MVBs). Because EVs potentially contribute to tumor progression, EV inhibitors are of interest as novel therapeutics. We screened a fungal natural product library. Using cancer cells engineered to secrete luciferase-labeled EVs, we identified asteltoxin, which inhibits mitochondrial ATP synthase, as an EV inhibitor. Low concentrations of asteltoxin inhibited EV secretion without inducing mitochondrial damage. Asteltoxin attenuated cellular ATP levels and induced AMPK-mediated mTORC1 inactivation. Consequently, MiT/TFE transcription factors are translocated into the nucleus, promoting transcription of lysosomal genes and lysosome activation. Electron microscopy analysis revealed that the number of lysosomes increased relative to that of MVBs and the level of EVs decreased after treatment with asteltoxin or rapamycin, an mTORC1 inhibitor. These findings suggest that asteltoxin represents a new type of EV inhibitor that controls MVB fate.

SUBMITTER: Mitani F

PROVIDER: S-EPMC9035176 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Mitani Fumie F Lin Jianyu J Sakamoto Tatsuya T Uehara Ryo R Hikita Tomoya T Yoshida Takuya T Setiawan Andi A Arai Masayoshi M Oneyama Chitose C

Scientific reports 20220423 1

Cancer cells secrete aberrantly large amounts of extracellular vesicles (EVs) including exosomes, which originate from multivesicular bodies (MVBs). Because EVs potentially contribute to tumor progression, EV inhibitors are of interest as novel therapeutics. We screened a fungal natural product library. Using cancer cells engineered to secrete luciferase-labeled EVs, we identified asteltoxin, which inhibits mitochondrial ATP synthase, as an EV inhibitor. Low concentrations of asteltoxin inhibite ...[more]

PMID: 35461323

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

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

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