Sulfisoxazole inhibits the secretion of small extracellular vesicles by targeting the endothelin receptor A

  • Nat Commun. 2019 Mar 27;10(1):1387. doi: 10.1038/s41467-019-09387-4.
Eun-Ju Im  1 ,  Chan-Hyeong Lee  1 ,  Pyong-Gon Moon  1 ,  Gunassekaran Gowri Rangaswamy  2 ,  Byungheon Lee  2 ,  Jae Man Lee  2 ,  Jae-Chul Lee  3 ,  Jun-Goo Jee  4 ,  Jong-Sup Bae  4 ,  Taeg-Kyu Kwon  5 ,  Keon-Wook Kang  6 ,  Myeong-Seon Jeong  7  8 ,  Joo-Eun Lee  8 ,  Hyun-Suk Jung  8 ,  Hyun-Joo Ro  9 ,  Sangmi Jun  9 ,  Wonku Kang  10 ,  Seung-Yong Seo  11 ,  Young-Eun Cho  12 ,  Byoung-Joon Song  12 ,  Moon-Chang Baek  13
Affiliations
  • 1. Department of Molecular Medicine, CMRI, Exosome Convergence Research Center (ECRC), School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
  • 2. Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
  • 3. Department of Microbiology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
  • 4. Research Institute of Pharmaceutical Researches, College of Pharmacy, Kyungpook National University, Daegu, 41566, Republic of Korea.
  • 5. Department of Immunology and School of Medicine, Keimyung University, Daegu, 42601, Republic of Korea.
  • 6. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
  • 7. Chuncheon Center, Korean Basic Science Institute, Gangwon-do, 24341, Republic of Korea.
  • 8. Department of Biochemistry, College of Natural Sciences, Kangwon National University, Gangwon-do, 24341, Republic of Korea.
  • 9. Drug & Disease Target Group, Korea Basic Science Institute, Cheongju, 28119, Republic of Korea.
  • 10. College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.
  • 11. College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, 21936, Republic of Korea.
  • 12. Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, 20892, MD, USA.
  • 13. Department of Molecular Medicine, CMRI, Exosome Convergence Research Center (ECRC), School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea. [email protected].
PMID: 30918259 DOI: 10.1038/s41467-019-09387-4
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.

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