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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In the current core analysis, spatial homogenization is utilized to reduce the computational time. The discontinuity factor (DF) is one of the effective correction factors to reduce spatial homogenization error. The DF in diffusion equation is widely used; on the other hand the DF in transport equation has not been put to practical use although several efforts have been carried out. In this paper, the angular flux discontinuity factor (AFDF) as the DF for the integro-differential transport equation (e.g., the discrete-ordinate method, the method of characteristics) is theoretically described and its applicability is discussed. The AFDF is used to preserve the region-wise neutron leakage at each spatial mesh and defined as a ratio of heterogeneous and homogeneous angular fluxes at the homogenized region surface. In a homogeneous calculation with the AFDF, the angular flux is discontinuous at the region surface. In this paper the applicability of the AFDF to fuel pin cell homogenization is verified for one-dimensional slab geometry. As a result of this verification, it is confirmed that the AFDF has the capability to reduce the spatial homogenization error of fuel pin cell homogenization.