MEK/ERK-mediated oncogenic signals promote secretion of extracellular vesicles by controlling lysosome function.
Tomoya HikitaRyo UeharaReina E ItohFumie MitaniMamiko MiyataTakuya YoshidaRui YamaguchiChitose OneyamaPublished in: Cancer science (2022)
Cancer cells secrete large amounts of extracellular vesicles (EVs) originating from multivesicular bodies (MVBs). Mature MVBs fuse either with the plasma membrane for release as EVs, often referred as to exosomes or with lysosomes for degradation. However, the mechanisms regulating MVB fate remain unknown. Here, we investigated the regulators of MVB fate by analyzing the effects of signaling inhibitors on EV secretion from cancer cells engineered to secrete luciferase-labeled EVs. Inhibition of the oncogenic MEK/ERK pathway suppressed EV release and activated lysosome formation. MEK/ERK-mediated lysosomal inactivation impaired MVB degradation, resulting in increased EV secretion from cancer cells. Moreover, MEK/ERK inhibition prevented c-MYC expression and induced the nuclear translocation of MiT/TFE transcription factors, thereby promoting the activation of lysosome-related genes, including the gene encoding a subunit of vacuolar-type H + -ATPase, which is responsible for lysosomal acidification and function. Furthermore, c-MYC upregulation was associated with lysosomal gene downregulation in MEK/ERK-activated renal cancer cells/tissues. These findings suggest that the MEK/ERK/c-MYC pathway controls MVB fate and promotes EV production in human cancers by inactivating lysosomal function.
Keyphrases
- pi k akt
- signaling pathway
- cell proliferation
- transcription factor
- endothelial cells
- fluorescent probe
- stem cells
- genome wide
- mesenchymal stem cells
- dna methylation
- genome wide identification
- bone marrow
- computed tomography
- diabetic rats
- young adults
- high glucose
- oxidative stress
- positron emission tomography
- binding protein
- single molecule
- endoplasmic reticulum