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

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 a natural product resource and identify its mechanism-of-action. Identified are the significant anti-cancer effect and underlying mechanism of SFN, an isothiocyanate derived from cruciferous vegetables, through RNA sequencing, western blot, and immunofluorescent assays. It is found that SFN inhibits proliferation of ESCC cells through inducing senescence. Mechanistically, SFN induces reactive oxygen species (ROS) via disrupting the balance between glutathione and oxidized glutathione, 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. 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.