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

Abstract

ScopeThe 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.Methods and ResultsIdentified 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.ConclusionsThis 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.

GSH Levels Serve As a Biological Redox Switch Regulating Sulforaphane-Induced Cell Fate in Human Lens Cells

“…The complete protection of NAC from other SFN-induced cellular events, such as mitochondrial dysfunction, ERS, DNA damage, and autophagy, and the protection yielded by sodium pyruvate against impaired Δψ m collectively indicate an important role for ROS in these SFN-induced phenomena. The current findings are comparable to those of previous studies, in which SFN induced ROS-dependent Δψ m perturbations in human leukemia cells, 41 ROS-dependent DNA damage and responses in umbilical vein endothelial cells and esophageal cancer cells, 39 , 42 and ROS-dependent autophagy in colon, prostate, and esophageal cancer cells. 37 , 39 , 43 Moreover, although others have demonstrated the induction of ERS by SFN, 11 , 44 the current work provides the first evidence that the induction is ROS dependent.…”

“…In several cancer cell lines, SFN-induced cell cycle arrest or cell death was also prevented by alleviating ROS levels, such as by overexpressing catalase, an endogenous antioxidant, or supplementing cells with NAC or (2R, 4R)-4-aminopyrrolidine-2,4-dicarboxylate (ADPC), a ROS inhibitor. 23 , 36 – 39 The Nrf2 pathway regulates detoxification and antioxidant defense processes, and SFN is a potent activator of Nrf2. 4 Nonetheless, the elevation of Nrf2 activity beyond physiological levels can be detrimental to cells.…”

Sulforaphane Impact on Reactive Oxygen Species (ROS) in Bladder Carcinoma

“…No publications are available dealing with the influence of SFN on Nrf2 in bladder cancer cells (where Nrf2 downregulation would be expected). SFN activated Nrf2 in normal esophageal epithelial cells, but not in esophageal cancer cells [ 128 ], which seems to be in accordance with the biphasic characteristics of SFN. However, inhibition of cell proliferation and invasion of pancreatic cancer cell lines by SFN was associated with translocation of Nrf2 from the cytoplasm into the nucleus [ 129 ].…”

“…A similar mode of action may hold true for SFN as well. In fact, induction of apoptosis and senescence of esophageal squamous cell carcinoma cells by SFN was triggered by a ROS-mediated mTOR inactivation [ 128 ].…”

The Significance of Exosomes in Pathogenesis, Diagnosis, and Treatment of Esophageal Cancer

“… 95 , 96 Zheng et al identified sulforaphane (SFN) could inhibit ESCC cell proliferation via inducing senescence. 97 Meanwhile, SFN caused autophagy dysfunction and exosome release in reactive oxygen species (ROS)-mammalian target of rapamycin (mTOR)-dependent manner participated in triggering paracrine senescence. The modulating autophagy and the exosome-mediated paracrine senescence represents a promising strategy for ESCC treatment.…”