Abstract
Hydrogen sulfide (H2S) is widely recognized as the third endogenous gas signaling molecule and may play a key role in cancer biological processes. ADT-OH (5-(4-hydroxyphenyl)−3H-1,2-dithiocyclopentene-3-thione) is one of the most widely used organic donors for the slow release of H2S and considered to be a potential anticancer compound. In this study, we investigated the antimetastatic effects of ADT-OH in highly metastatic melanoma cells. A tail-vein-metastasis model was established by injecting B16F10 and A375 cells into the tail veins of mice, whereas a mouse footpad-injection model was established by injecting B16F10 cells into mouse footpads. We showed that administration of ADT-OH significantly inhibited the migration and invasion of melanoma cells in the three different animal models. We further showed that ADT-OH dose-dependently inhibited the migration and invasion of B16F10, B16F1 and A375 melanoma cells as evaluated by wound healing and Transwell assays in vitro. LC-MS/MS and bioinformatics analyses revealed that ADT-OH treatment inhibited the EMT process in B16F10 and A375 cells by reducing the expression of FAK and the downstream response protein Paxillin. Overexpression of FAK reversed the inhibitory effects of ADT-OH on melanoma cell migration. Moreover, after ADT-OH treatment, melanoma cells showed abnormal expression of the H2S-producing enzymes CSE/CBS and the AKT signaling pathways. In addition, ADT-OH significantly suppressed the proliferation of melanoma cells. Collectively, these results demonstrate that ADT-OH inhibits the EMT process in melanoma cells by suppressing the CSE/CBS and FAK signaling pathways, thereby exerting its antimetastatic activity. ADT-OH may be used as an antimetastatic agent in the future.
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Acknowledgements
This study was supported by grants from the Chinese National Natural Sciences Foundation (81773099, 81630092 and 82130106), Department of Science and Technology of Jiangsu Province (BK20192005) and the program B for Outstanding PhD candidate of Nanjing University (202001B051).
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ZCH, HQZ and JC (Jian Cheng) designed the outline of the paper. HQZ revised this paper. FFC and HRX contributed equally to this work. FFC and HRX performed most of the experiments in this study. FFC wrote the paper and prepared the Figures. SHY, PL, YYL, JC (Jia Chen), ZQB and HSS helped with the cell related experiments. SHY and PL helped with the experiments using animals. All authors have read and approved the final version of this paper.
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Animal welfare and experimental procedures were performed in strict accordance with high standard animal welfare and other related ethical regulations approved by the Nanjing University Animal Care and Use Committee.
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Cai, Ff., Xu, Hr., Yu, Sh. et al. ADT-OH inhibits malignant melanoma metastasis in mice via suppressing CSE/CBS and FAK/Paxillin signaling pathway. Acta Pharmacol Sin 43, 1829–1842 (2022). https://doi.org/10.1038/s41401-021-00799-x
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DOI: https://doi.org/10.1038/s41401-021-00799-x
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