Sulfisoxazole inhibits the secretion of small extracellular vesicles by targeting the endothelin receptor A
Authors: Keon-Wook Kang
Jong-Sup Bae
Myeong-Seon Jeong
Wonku Kang
Moon-Chang Baek
Hyun-Suk Jung
Jae-Chul Lee
Chan-Hyeong Lee
Jae Man Lee
Pyong-Gon Moon
Young-Eun Cho
Byoung-Joon Song
Sangmi Jun
Eun-Ju Im
Joo-Eun Lee
Jun-Goo Jee
Hyun-Joo Ro
Taeg-Kyu Kwon
Gunassekaran Gowri Rangaswamy
Byungheon Lee
Seung-Yong Seo
Journal: Nature Communications (2019)
Discipline: Multidisciplinary
Keywords: exosomes; cancer progression; metastasis; inhibitors; sulfisoxazole
Affiliations: Department of Molecular Medicine, CMRI, Exosome Convergence Research Center (ECRC), School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea., Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea., Department of Microbiology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea., Research Institute of Pharmaceutical Researches, College of Pharmacy, Kyungpook National University, Daegu, 41566, Republic of Korea., Department of Immunology and School of Medicine, Keimyung University, Daegu, 42601, Republic of Korea., College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea., Chuncheon Center, Korean Basic Science Institute, Gangwon-do, 24341, Republic of Korea., Department of Biochemistry, College of Natural Sciences, Kangwon National University, Gangwon-do, 24341, Republic of Korea., Drug & Disease Target Group, Korea Basic Science Institute, Cheongju, 28119, Republic of Korea., College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea., College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, 21936, Republic of Korea., Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, 20892, MD, USA., Department of Molecular Medicine, CMRI, Exosome Convergence Research Center (ECRC), School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea. .

Abstract:  Inhibitors of the secretion of cancer exosomes, which promote cancer progression and metastasis, may not only accelerate exosome biology research but also offer therapeutic benefits for cancer patients. Here we identify sulfisoxazole (SFX) as an inhibitor of small extracellular vesicles (sEV) secretion from breast cancer cells through interference with endothelin receptor A (ETA). SFX, an FDA-approved oral antibiotic, showed significant anti-tumor and anti-metastatic effects in mouse models of breast cancer xenografts, the reduced expression of proteins involved in biogenesis and secretion of sEV, and triggered co-localization of multivesicular endosomes with lysosomes for degradation. We demonstrate the important role of ETA, as target of SFX, by gain- and loss-of-function studies of the ETA protein, through a direct binding assay, and pharmacological and genetic approaches. These findings may provide a foundation for sEV-targeted cancer therapies and the mechanistic studies on sEV biology. 

Retracted: No

PubPeer comments:
 Figure 1C: the two beta-actin panels are more similar than expected. Some stripes in the background look very similar. Shown with red boxes.  Figure 3B: the 1E8-HVIMax photo appears to show an area that is unexpectedly similar to an area in the 2B4-L photo. Shown with blue boxes.  , 
 Correction, [February 2020](http: ar.iiarjournals.org content 40 2 1183.1):  Figure 1C should be replaced by: (http: ar.iiarjournals.org content 40 2 1183.1 F1.medium.gif) A second correction [was published at the same time but is paywalled](http: ar.iiarjournals.org content 40 2 1183.2.figures-only), with only the Figure visible - presumably it replaces Fig 3B. (http: ar.iiarjournals.org content 40 2 1183.2 F1.medium.gif) , 
 The replacement for Figure 3B is not without problems either. It still appears to show an overlap between the same two panels, just in a different area. One could have hoped the authors would not make the same mistake twice?  ,