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Everolimus exerts anticancer effects through inhibiting the interaction of matrix metalloproteinase-7 with syndecan-2 in colon cancer cells
- Title
- Everolimus exerts anticancer effects through inhibiting the interaction of matrix metalloproteinase-7 with syndecan-2 in colon cancer cells
- Authors
- Eok-Soo; Oh; Lee; Seohyeon; Jang; Bohee; Hwang; Jisun; Yejin; Cho; Subin; Yang; Hyeonju; Yun; Ji-Hye; Shin; Dong Hae; Weontae
- Ewha Authors
- 오억수; 신동해; 황지선; 장보희
- SCOPUS Author ID
- 오억수; 신동해; 황지선; 장보희
- Issue Date
- 2024
- Journal Title
- American Journal of Physiology - Cell Physiology
- ISSN
- 0363-6143
- Citation
- American Journal of Physiology - Cell Physiology vol. 326, no. 4, pp. C1067 - C1079
- Keywords
- colon cancer; everolimus; matrix metalloproteinase-7; syndecan 2; protein drug interaction
- Publisher
- American Physiological Society
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- Previous work showed that matrix metalloproteinase-7 (MMP-7) regulates colon cancer activities through an interaction with syndecan-2 (SDC-2) and SDC-2-derived peptide that disrupts this interaction and exhibits anticancer activity in colon cancer. Here, to identify potential anticancer agents, a library of 1,379 Food and Drug Administration (FDA)-approved drugs that interact with the MMP-7 prodomain were virtually screened by protein-ligand docking score analysis using the GalaxyDock3 program. Among five candidates selected based on their structures and total energy values for interacting with the MMP-7 prodomain, the known mechanistic target of rapamycin kinase (mTOR) inhibitor, everolimus, showed the highest binding affinity and the strongest ability to disrupt the interaction of the MMP-7 prodomain with the SDC-2 extracellular domain in vitro. Everolimus treatment of the HCT116 human colon cancer cell line did not affect the mRNA expression levels of MMP-7 and SDC-2 but reduced the adhesion of cells to MMP-7 prodomain-coated plates and the cell-surface localization of MMP-7. Thus, everolimus appears to inhibit the interaction between MMP-7 and SDC-2. Everolimus treatment of HCT116 cells also reduced their gelatin-degradation activity and anticancer activities, including colony formation. Interestingly, cells treated with sirolimus, another mTOR inhibitor, triggered less gelatin-degradation activity, suggesting that this inhibitory effect of everolimus was not due to inhibition of the mTOR pathway. Consistently, everolimus inhibited the colony-forming ability of mTOR-resistant HT29 cells. Together, these data suggest that, in addition to inhibiting mTOR signaling, everolimus exerts anticancer activity by interfering with the interaction of MMP-7 and SDC-2, and could be a useful therapeutic anticancer drug for colon cancer. © 2024 the American Physiological Society.
- DOI
- 10.1152/ajpcell.00669.2023
- Appears in Collections:
- 자연과학대학 > 생명과학전공 > Journal papers
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