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A high-content screen for small-molecule regulators of epithelial cell-adhesion molecule (EpCAM) cleavage yields a robust inhibitor.
J. Biol. Chem. 293, 8994-9005 (2018)
Epithelial cell-adhesion molecule (EpCAM) is a transmembrane protein that regulates cell cycle progression and differentiation and is overexpressed in many carcinomas. The EpCAM-induced mitogenic cascade is activated via regulated intramembrane proteolysis (RIP) of EpCAM by ADAM and -secretases, generating the signaling-active intracellular domain EpICD. Because of its expression pattern and molecular function, EpCAM is a valuable target in prognostic and therapeutic approaches for various carcinomas. So far, several immunotherapeutic strategies have targeted the extracellular domain of EpCAM. However, targeting the intracellular signaling cascade of EpCAM holds promise for specifically interfering with EpCAM’s proliferation-stimulating signaling cascade. Here, using a yellow fluorescence protein–tagged version of the C-terminal fragment of EpCAM, we established a high-content screening (HCS) of a small-molecule compound library (n 27,280) and characterized validated hits that target EpCAM signaling. In total, 128 potential inhibitors were initially identified, of which one compound with robust inhibitory effects on RIP of EpCAM was analyzed in greater detail. In summary, our study demonstrates that the development of an HCS for small-molecule inhibitors of the EpCAM signaling pathway is feasible. We propose that this approach may also be useful for identifying chemical compounds targeting other disorders involving membrane cleavage-dependent signaling pathways.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Anticancer Drug ; Cell Signaling ; Epithelial Cell Adhesion Molecule (epcam) ; High-throughput Screening (hts) ; Intramembrane Proteolysis; Cell-line Thp-1; In-vitro; Hacat Keratinocytes; Alkaloid Berberine; Dendritic Cells; Injury; Skin; Sensitization; Expression; Toxicity
ISSN (print) / ISBN
0021-9258
e-ISSN
1083-351X
Quellenangaben
Volume: 293,
Issue: 23,
Pages: 8994-9005
Publisher
American Society for Biochemistry and Molecular Biology
Publishing Place
Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland
Non-patent literature
Publications
Reviewing status
Peer reviewed