ADT-OH inhibits malignant melanoma metastasis in mice via suppressing CSE/CBS and FAK/Paxillin signaling pathway  

作　　者：Fang-fang Cai Huang-ru Xu Shi-hui Yu Ping Li Yan-yan Lu Jia Chen Zhi-qian Bi Hui-song Sun Jian Cheng Hong-qin Zhuang Zi-chun Hua 

机构地区：[1]The State Key Laboratory of Pharmaceutical Biotechnology,College of Life Sciences,Nanjing University,Nanjing 210008,China [2]School of Biopharmacy,China Pharmaceutical University,Nanjing 211198,China [3]Institute of Neuroscience,Soochow University,Suzhou 215031,China [4]Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc.,Changzhou 213164,China

出　　处：《Acta Pharmacologica Sinica》2022年第7期1829-1842,共14页中国药理学报（英文版）

基　　金：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);the program B for Outstanding PhD candidate of Nanjng University(202001B051).

摘　　要：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.

关 键 词：MELANOMA hydrogen sulfide ADT-OH EMT tumor metastasis FAK PAXILLIN CSE/CBS 

分 类 号：R739.5[医药卫生—肿瘤] R96[医药卫生—临床医学]