Kai Zheng1, Jingxin Ma1, Yifei Wang2, Zhendan He1,3, Kejun Deng4. 1. School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, P. R. China. 2. College of Life Science and Technology, Guangzhou Jinan Biomedicine Research and Development Center, Jinan University, Guangzhou, 510632, P. R. China. 3. Guangdong Key laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen, 518060, P. R. China. 4. School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, 610054, P. R. China.
Abstract
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 a natural product resource and identify its mechanism-of-action. METHODS AND RESULTS: 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. 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.
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 a natural product resource and identify its mechanism-of-action. METHODS AND RESULTS: 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. 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.
Authors: Thao Phuong Ngoc Huynh; Richard P Bowater; Federico Bernuzzi; Shikha Saha; I Michael Wormstone Journal: Invest Ophthalmol Vis Sci Date: 2021-12-01 Impact factor: 4.799