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Small Molecule Inhibitors Target the Tissue Transglutaminase and Fibronectin Interaction
- Source :
- PLoS ONE, PLoS ONE, Vol 9, Iss 2, p e89285 (2014)
- Publication Year :
- 2014
- Publisher :
- Public Library of Science, 2014.
-
Abstract
- Tissue transglutaminase (TG2) mediates protein crosslinking through generation of e-(γ-glutamyl) lysine isopeptide bonds and promotes cell adhesion through interaction with fibronectin (FN) and integrins. Cell adhesion to the peritoneal matrix regulated by TG2 facilitates ovarian cancer dissemination. Therefore, disruption of the TG2-FN complex by small molecules may inhibit cell adhesion and metastasis. A novel high throughput screening (HTS) assay based on AlphaLISA™ technology was developed to measure the formation of a complex between His-TG2 and the biotinylated FN fragment that binds TG2 and to discover small molecules that inhibit this protein-protein interaction. Several hits were identified from 10,000 compounds screened. The top candidates selected based on >70% inhibition of the TG2/FN complex formation were confirmed by using ELISA and bioassays measuring cell adhesion, migration, invasion, and proliferation. In conclusion, the AlphaLISA bead format assay measuring the TG2-FN interaction is robust and suitable for HTS of small molecules. One compound identified from the screen (TG53) potently inhibited ovarian cancer cell adhesion to FN, cell migration, and invasion and could be further developed as a potential inhibitor for ovarian cancer dissemination.
- Subjects :
- Tissue transglutaminase
Cancer Treatment
lcsh:Medicine
Biochemistry
Cell Movement
Drug Discovery
Molecular Cell Biology
Tumor Cells, Cultured
Protein Interaction Maps
lcsh:Science
Ovarian Neoplasms
Multidisciplinary
Cell adhesion molecule
Cell migration
Cell biology
Extracellular Matrix
Ovarian Cancer
Oncology
Biotinylation
Medicine
Female
Research Article
Drugs and Devices
Drug Research and Development
Integrin
Blotting, Western
Enzyme-Linked Immunosorbent Assay
Biology
Small Molecule Libraries
GTP-Binding Proteins
Cell Adhesion
Humans
Protein Glutamine gamma Glutamyltransferase 2
Cell adhesion
Protein Interactions
Extracellular Matrix Adhesions
Cell Proliferation
Wound Healing
Transglutaminases
Cell growth
lcsh:R
Proteins
Cancers and Neoplasms
Molecular biology
Fibronectins
High-Throughput Screening Assays
Fibronectin
Small Molecules
biology.protein
lcsh:Q
Gynecological Tumors
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 9
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....ad56251496911cd6d79eb3cbb572572d