Sulforaphane Inhibits Autophagy and Induces Exosome‐Mediated Paracrine Senescence via Regulating mTOR/TFE3

SCOPE The development of novel compounds that trigger non-apoptotic cell death may represent alternative therapeutic strategies for esophageal squamous cell carcinoma (ESCC) treatment. Cellular senescence suppresses tumorigenesis by halting the proliferation of tumor cells, implying the induction of senescence as a promising anticancer strategy, especially when combined with senolytic agents that specially kill senescent cells. This study is designed to screen novel anti-ESCC compounds from natural product resource and identify its mechanism-of-action. METHODS AND RESULTS We identify the significant anti-cancer effect and the underlying mechanism of SFN, an isothiocyanate derived from cruciferous vegetables, through RNA-seq, western blot and immunofluorescent assays. We find that SFN inhibits proliferation of ESCC cells through inducing senescence. Mechanistically, SFN induces reactive oxygen species (ROS) via disrupting the balance between glutathione (GSH) and oxidized glutathione (GSSG), leading to DNA damage. In addition, ROS deregulates autophagy and promotes lysosome abnormal biogenesis through regulating mTOR/TFE3 axis. Finally, the inhibited autophagic flux facilitates exosome production, resulting in exosome-mediated paracrine senescence. CONCLUSIONS This study suggests the important roles of autophagy and exosome-mediated paracrine senescence in cancer therapy and highlights SFN as a potent anti-ESCC drug candidate. This article is protected by copyright. All rights reserved.