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

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

  • Sci Rep. 2022 Apr 23;12(1):6674. doi: 10.1038/s41598-022-10692-0.
Fumie Mitani # 1 2,  Jianyu Lin # 3,  Tatsuya Sakamoto 1 4,  Ryo Uehara 1,  Tomoya Hikita 1,  Takuya Yoshida 5,  Andi Setiawan 6,  Masayoshi Arai 7,  Chitose Oneyama 8 9 10 11
Affiliations

Affiliations

  • 1 Division of Cancer Cell Regulation, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan.
  • 2 Department of Oncology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Japan.
  • 3 Laboratory of Natural Products for Drug Discovery, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
  • 4 Department of Target and Drug Discovery, Graduate School of Medicine, Nagoya University, Showa-ku, Nagoya, Japan.
  • 5 Laboratory of Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
  • 6 Department of Chemistry, Faculty of Mathematics and Natural Sciences, Lampung University, Bandar Lampung, Indonesia.
  • 7 Laboratory of Natural Products for Drug Discovery, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan. araim@phs.osaka-u.ac.jp.
  • 8 Division of Cancer Cell Regulation, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan. coneyama@aichi-cc.jp.
  • 9 Department of Oncology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Japan. coneyama@aichi-cc.jp.
  • 10 Department of Target and Drug Discovery, Graduate School of Medicine, Nagoya University, Showa-ku, Nagoya, Japan. coneyama@aichi-cc.jp.
  • 11 JST, PRESTO, Nagoya, Japan. coneyama@aichi-cc.jp.
  • # Contributed equally.
PMID: 35461323 DOI: 10.1038/s41598-022-10692-0
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.

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