Lysyl oxidase-like 4 promotes the invasiveness of triple-negative breast cancer cells by orchestrating the invasive machinery formed by annexin A2 and S100A11 on the cell surface

• Published in: Frontiers in oncology Vol. 14; p. 1371342
• Main Authors: Takahashi, Tetta, Tomonobu, Nahoko, Kinoshita, Rie, Yamamoto, Ken-Ichi, Murata, Hitoshi, Komalasari, Ni Luh Gede Yoni, Chen, Youyi, Jiang, Fan, Gohara, Yuma, Ochi, Toshiki, Ruma, I Made Winarsa, Sumardika, I Wayan, Zhou, Jin, Honjo, Tomoko, Sakaguchi, Yoshihiko, Yamauchi, Akira, Kuribayashi, Futoshi, Kondo, Eisaku, Inoue, Yusuke, Futami, Junichiro, Toyooka, Shinichi, Zamami, Yoshito, Sakaguchi, Masakiyo
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 26.03.2024
• Subjects: annexin A2; breast cancer; cancer microenvironment; lysyl oxidase; Oncology; plasmin; S100A11; annexin A2; breast cancer; cancer microenvironment; lysyl oxidase; plasmin; S100A11
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2024.1371342

Our earlier research revealed that the secreted lysyl oxidase-like 4 (LOXL4) that is highly elevated in triple-negative breast cancer (TNBC) acts as a catalyst to lock annexin A2 on the cell membrane surface, which accelerates invasive outgrowth of the cancer through the binding of integrin-β1 on the cell surface. However, whether this machinery is subject to the LOXL4-mediated intrusive regulation remains uncertain. Cell invasion was assessed using a transwell-based assay, protein-protein interactions by an immunoprecipitation-Western blotting technique and immunocytochemistry, and plasmin activity in the cell membrane by gelatin zymography. We revealed that cell surface annexin A2 acts as a receptor of plasminogen via interaction with S100A10, a key cell surface annexin A2-binding factor, and S100A11. We found that the cell surface annexin A2/S100A11 complex leads to mature active plasmin from bound plasminogen, which actively stimulates gelatin digestion, followed by increased invasion. We have refined our understanding of the role of LOXL4 in TNBC cell invasion: namely, LOXL4 mediates the upregulation of annexin A2 at the cell surface, the upregulated annexin 2 binds S100A11 and S100A10, and the resulting annexin A2/S100A11 complex acts as a receptor of plasminogen, readily converting it into active-form plasmin and thereby enhancing invasion.