Abstract
Asparagine endopeptidase (AEP), also called legumain, is currently the only known cysteine protease that specifically cleaves peptide bonds in asparaginyl residue in the mammalian genome. Since 2003, AEP has been reported to be widely expressed in a variety of carcinomas and is considered a potential therapeutic target. In the following years, researchers intensively investigated the substrates of AEP and the mechanism of AEP in partial tumors. With the identification of substrate proteins such as P53, integrin αvβ3, MMP-2, and MMP-9, the biochemical mechanism of AEP in carcinomas is also more precise. This review will clarify the probable mechanisms of AEP in the progression of breast carcinoma, glioblastoma, gastric carcinoma, and epithelial ovarian carcinoma. This review will also discuss the feasibility of targeted therapy with AEP inhibitor (AEPI) in these carcinomas.
Highlights
We focus on four carcinomas that have been studied to a greater extent, including glioblastomas (GBMs), breast carcinomas, epithelial ovarian carcinomas, and gastric carcinomas
Combined with the biochemical mechanisms of Asparagine endopeptidase (AEP) described in our review, the following therapeutic strategies are proposed for consideration: (i) a combination of medications consisting of signaling pathway inhibitors and AEP inhibitor (AEPI), which may improve the efficiency of chemotherapy; (ii) a multi-peptide DNA vaccine including AEP, tumor necrosis factor receptor-associated factor 6 (TRAF6), and other potential target proteins; (iii) the development of prodrugs together with two chemotherapeutic agents
Pathway inhibitors combined with AEPI. It was found in an analysis of clinical samples of the integrin α5β1/AEP complex that the level of the integrin α5β1/AEP complex was elevated in both the serum and ascites of patients, and it was positively correlated with poor prognosis
Summary
Asparagine endopeptidase (AEP) is a cysteine protease that was initially discovered in leguminous seeds in the early 1980s and was first isolated and identified in mammals in. Active site residues His148 , Cys189 , and Asn of the catalytic domain are in close spatial proximity to each other, and are essential for the enzymatic activity of AEP [5,6] (Figure 1). Pro-AEP (53 kDa) is autoactivated at pH 4.5~5.5 into an intermediate form (46/47 kDa) through self-cleavage at Asn323. Asp303/309 (pH ≤ 4.0) [9,10] Both the intermediate form (46/47 kDa) and the mature form (36 kDa) of AEP possess similar enzymatic activities, and both of them can be inhibited by the endogenous proteinase [10]. Autocatalytic processing at the Asn323 site is reversible in mammals, and an already proteolytically activated AEP can be converted back into the latent zymogen state through auto-ligation [15]. AEPI is the most promising chemotherapeutic agent for targeting AEP
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