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

Eun-Ju Im, Chan-Hyeong Lee, Pyong-Gon Moon, Gunassekaran Gowri Rangaswamy, Byungheon Lee, Jae Man Lee, Jae-Chul Lee, Jun-Goo Jee, Jong-Sup Bae, Taeg-Kyu Kwon, Keon-Wook Kang, Myeong-Seon Jeong, Joo-Eun Lee, Hyun-Suk Jung, Hyun-Joo Ro, Sangmi Jun, Wonku Kang, Seung-Yong Seo, Young-Eun Cho, Byoung-Joon Song and Moon-Chang Baek ()
Additional contact information
Eun-Ju Im: Kyungpook National University
Chan-Hyeong Lee: Kyungpook National University
Pyong-Gon Moon: Kyungpook National University
Gunassekaran Gowri Rangaswamy: Kyungpook National University
Byungheon Lee: Kyungpook National University
Jae Man Lee: Kyungpook National University
Jae-Chul Lee: Kyungpook National University
Jun-Goo Jee: Kyungpook National University
Jong-Sup Bae: Kyungpook National University
Taeg-Kyu Kwon: Keimyung University
Keon-Wook Kang: Seoul National University
Myeong-Seon Jeong: Korean Basic Science Institute
Joo-Eun Lee: Kangwon National University
Hyun-Suk Jung: Kangwon National University
Hyun-Joo Ro: Korea Basic Science Institute
Sangmi Jun: Korea Basic Science Institute
Wonku Kang: Chung-Ang University
Seung-Yong Seo: Gachon University
Young-Eun Cho: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Byoung-Joon Song: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Moon-Chang Baek: Kyungpook National University

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09387-4

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