MEK/ERK‐mediated oncogenic signals promote secretion of extracellular vesicles by controlling lysosome function. Issue 4 (13th February 2022)

• Record Type: Journal Article
• Authors: Hikita, Tomoya; Uehara, Ryo; Itoh, Reina E.; Mitani, Fumie; Miyata, Mamiko; Yoshida, Takuya; Yamaguchi, Rui; Oneyama, Chitose
• Is Part Of: Cancer science. Volume 113:Issue 4(2022)
• Page Start: 1264
• Page End: 1276
• Publication Date: 2022-02-13
• Subjects: c‐MYC -- extracellular vesicles -- lysosome -- MEK/ERK -- renal cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.15288
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: 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. Abstract : MEK/ERK‐mediated oncogenic signals promote EV secretion by lysosomal inactivation. MEK/ERK activation induces c‐MYC expression and suppresses nuclear localization of MiT/TFE transcription factors, leading to the downregulation of lysosome‐related genes critical for lysosome function.