Esomeprazole inhibits the lysosomal cysteine protease legumain to prevent cancer metastasis
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PRECLINICAL STUDIES
Esomeprazole inhibits the lysosomal cysteine protease legumain to prevent cancer metastasis Tian Zhao 1 & Yujie Liu 1 & Yanfei Hao 1 & Wei Zhang 1 & Li Tao 1 & Dong Wang 1 & Yuyin Li 1 & Zhenxing Liu 1 & Edward A McKenzie 2 & Qing Zhao 1 & Aipo Diao 1 Received: 17 August 2020 / Accepted: 21 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Legumain is a newly discovered lysosomal cysteine protease that can cleave asparagine bonds and plays crucial roles in regulating immunity and cancer metastasis. Legumain has been shown to be highly expressed in various solid tumors, within the tumor microenvironment and its levels are directly related to tumor metastasis and poor prognosis. Therefore, legumain presents as a potential cancer therapeutic drug target. In this study, we have identified esomeprazole and omeprazole as novel legumain small molecule inhibitors by screening an FDA approved-drug library. These compounds inhibited enzyme activity of both recombinant and endogenous legumain proteins with esomeprazole displaying the highest inhibitory effect. Further molecular docking analysis also indicated that esomeprazole, the S- form of omeprazole had the most stable binding to legumain protein compared to R-omeprazole. Transwell assay data showed that esomeprazole and omeprazole reduced MDA-MB-231 breast cancer cell invasion without effecting cell viability. Moreover, an in vivo orthotopic transplantation nude mouse model study showed that esomeprazole reduced lung metastasis of MDA-MB-231 breast cancer cells. These results indicated that esomeprazole has the exciting potential to be used in anti-cancer therapy by preventing cancer metastasis via the inhibition of legumain enzyme activity.
Keywords Legumain . Esomeprazole . Inhibitor . Cancer metastasis . Breast cancer
Introduction Legumain is a newly discovered lysosomal cysteine protease that can specifically cleave asparagine bonds and has been shown to play crucial roles in regulating immunity and cancer metastasis [1]. The human Legumain gene encodes an inactive proenzyme of 433 amino acids, and the 56 kDa pro-enzyme undergoes a low pH dependent autocatalytic activation to
* Qing Zhao [email protected] * Aipo Diao [email protected] 1
Key Laboratory of Industrial Fermentation Microbiology of the Ministry of Education, School of Biotechnology, Tianjin Economic and Technological Development Area (TEDA), Tianjin University of Science and Technology, No. 29, 13th Avenue, Tianjin 300457, China
2
Manchester Institute of Biotechnology (MIB), Manchester University, Manchester M1 7DN, UK
release the active endopeptidase of 46 kDa and 36 kDa molecular weights [2, 3]. Legumain protein is highly conserved amongst biological species and is localized mainly to the endo-lysosomal system, but also found located on the cell surface and extracellular matrix. Overexpression of legumain was observed in many kinds of solid tumors and with a low to zero level background expression in normal tissue. Overexpress
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