Lithocholic acid is an Eph-ephrin ligand interfering with Eph-kinase activation.
Eph-ephrin system plays a central role in a large variety of human cancers. In fact, alterated expression and/or de-regulated function of Eph-ephrin system promotes tumorigenesis and development of a more aggressive and metastatic tumour phenotype. In particular EphA2 upregulation is correlated with...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3068151?pdf=render |
| _version_ | 1818147596857769984 |
|---|---|
| author | Carmine Giorgio Iftiin Hassan Mohamed Lisa Flammini Elisabetta Barocelli Matteo Incerti Alessio Lodola Massimiliano Tognolini |
| author_facet | Carmine Giorgio Iftiin Hassan Mohamed Lisa Flammini Elisabetta Barocelli Matteo Incerti Alessio Lodola Massimiliano Tognolini |
| author_sort | Carmine Giorgio |
| collection | DOAJ |
| description | Eph-ephrin system plays a central role in a large variety of human cancers. In fact, alterated expression and/or de-regulated function of Eph-ephrin system promotes tumorigenesis and development of a more aggressive and metastatic tumour phenotype. In particular EphA2 upregulation is correlated with tumour stage and progression and the expression of EphA2 in non-transformed cells induces malignant transformation and confers tumorigenic potential. Based on these evidences our aim was to identify small molecules able to modulate EphA2-ephrinA1 activity through an ELISA-based binding screening. We identified lithocholic acid (LCA) as a competitive and reversible ligand inhibiting EphA2-ephrinA1 interaction (Ki = 49 µM). Since each ephrin binds many Eph receptors, also LCA does not discriminate between different Eph-ephrin binding suggesting an interaction with a highly conserved region of Eph receptor family. Structurally related bile acids neither inhibited Eph-ephrin binding nor affected Eph phosphorylation. Conversely, LCA inhibited EphA2 phosphorylation induced by ephrinA1-Fc in PC3 and HT29 human prostate and colon adenocarcinoma cell lines (IC(50) = 48 and 66 µM, respectively) without affecting cell viability or other receptor tyrosine-kinase (EGFR, VEGFR, IGFR1β, IRKβ) activity. LCA did not inhibit the enzymatic kinase activity of EphA2 at 100 µM (LANCE method) confirming to target the Eph-ephrin protein-protein interaction. Finally, LCA inhibited cell rounding and retraction induced by EphA2 activation in PC3 cells. In conclusion, our findings identified a hit compound useful for the development of molecules targeting ephrin system. Moreover, as ephrin signalling is a key player in the intestinal cell renewal, our work could provide an interesting starting point for further investigations about the role of LCA in the intestinal homeostasis. |
| first_indexed | 2024-12-11T12:37:46Z |
| format | Article |
| id | doaj.art-0b355f8267b24ce7b13039c22bc5a2bf |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T12:37:46Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-0b355f8267b24ce7b13039c22bc5a2bf2022-12-22T01:07:04ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0163e1812810.1371/journal.pone.0018128Lithocholic acid is an Eph-ephrin ligand interfering with Eph-kinase activation.Carmine GiorgioIftiin Hassan MohamedLisa FlamminiElisabetta BarocelliMatteo IncertiAlessio LodolaMassimiliano TognoliniEph-ephrin system plays a central role in a large variety of human cancers. In fact, alterated expression and/or de-regulated function of Eph-ephrin system promotes tumorigenesis and development of a more aggressive and metastatic tumour phenotype. In particular EphA2 upregulation is correlated with tumour stage and progression and the expression of EphA2 in non-transformed cells induces malignant transformation and confers tumorigenic potential. Based on these evidences our aim was to identify small molecules able to modulate EphA2-ephrinA1 activity through an ELISA-based binding screening. We identified lithocholic acid (LCA) as a competitive and reversible ligand inhibiting EphA2-ephrinA1 interaction (Ki = 49 µM). Since each ephrin binds many Eph receptors, also LCA does not discriminate between different Eph-ephrin binding suggesting an interaction with a highly conserved region of Eph receptor family. Structurally related bile acids neither inhibited Eph-ephrin binding nor affected Eph phosphorylation. Conversely, LCA inhibited EphA2 phosphorylation induced by ephrinA1-Fc in PC3 and HT29 human prostate and colon adenocarcinoma cell lines (IC(50) = 48 and 66 µM, respectively) without affecting cell viability or other receptor tyrosine-kinase (EGFR, VEGFR, IGFR1β, IRKβ) activity. LCA did not inhibit the enzymatic kinase activity of EphA2 at 100 µM (LANCE method) confirming to target the Eph-ephrin protein-protein interaction. Finally, LCA inhibited cell rounding and retraction induced by EphA2 activation in PC3 cells. In conclusion, our findings identified a hit compound useful for the development of molecules targeting ephrin system. Moreover, as ephrin signalling is a key player in the intestinal cell renewal, our work could provide an interesting starting point for further investigations about the role of LCA in the intestinal homeostasis.http://europepmc.org/articles/PMC3068151?pdf=render |
| spellingShingle | Carmine Giorgio Iftiin Hassan Mohamed Lisa Flammini Elisabetta Barocelli Matteo Incerti Alessio Lodola Massimiliano Tognolini Lithocholic acid is an Eph-ephrin ligand interfering with Eph-kinase activation. PLoS ONE |
| title | Lithocholic acid is an Eph-ephrin ligand interfering with Eph-kinase activation. |
| title_full | Lithocholic acid is an Eph-ephrin ligand interfering with Eph-kinase activation. |
| title_fullStr | Lithocholic acid is an Eph-ephrin ligand interfering with Eph-kinase activation. |
| title_full_unstemmed | Lithocholic acid is an Eph-ephrin ligand interfering with Eph-kinase activation. |
| title_short | Lithocholic acid is an Eph-ephrin ligand interfering with Eph-kinase activation. |
| title_sort | lithocholic acid is an eph ephrin ligand interfering with eph kinase activation |
| url | http://europepmc.org/articles/PMC3068151?pdf=render |
| work_keys_str_mv | AT carminegiorgio lithocholicacidisanephephrinligandinterferingwithephkinaseactivation AT iftiinhassanmohamed lithocholicacidisanephephrinligandinterferingwithephkinaseactivation AT lisaflammini lithocholicacidisanephephrinligandinterferingwithephkinaseactivation AT elisabettabarocelli lithocholicacidisanephephrinligandinterferingwithephkinaseactivation AT matteoincerti lithocholicacidisanephephrinligandinterferingwithephkinaseactivation AT alessiolodola lithocholicacidisanephephrinligandinterferingwithephkinaseactivation AT massimilianotognolini lithocholicacidisanephephrinligandinterferingwithephkinaseactivation |