Small molecule inhibitors of ezrin inhibit the invasive phenotype of osteosarcoma cells
| Autor: | Aykut Üren, Sivanesan Dakshanamurthy, Chand Khanna, Sung-Hyeok Hong, Hyun-Shik Lee, Kevin Chen, Eric Glasgow, I Daar, Gw W. Kosturko, Gülay Bulut, Em M. Beauchamp, Ja A. Toretsky, Said Rahim |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Lung Neoplasms Morpholino Immunoprecipitation Xenopus Adamantane Antineoplastic Agents Bone Neoplasms macromolecular substances Biology Quinolones environment and public health Article Extracellular matrix Mice Ezrin Organ Culture Techniques Phenols Cell Movement Cell Line Tumor Genetics Animals Neoplasm Invasiveness Phosphorylation Molecular Biology Zebrafish Mice Inbred BALB C Osteosarcoma Kinase Chemotaxis Surface Plasmon Resonance Actin cytoskeleton Actins Cell biology Cytoskeletal Proteins Cell culture Cancer research Quinolines Female |
| Zdroj: | Oncogene. 31(3) |
| ISSN: | 1476-5594 |
| Popis: | Ezrin is a multifunctional protein that connects the actin cytoskeleton to the extracellular matrix through transmembrane proteins. High ezrin expression is associated with lung metastasis and poor survival in cancer. We screened small molecule libraries for compounds that directly interact with ezrin protein using surface plasmon resonance to identify lead compounds. The secondary functional assays used for lead compound selection included ezrin phosphorylation as measured by immunoprecipitation and in vitro kinase assays, actin binding, chemotaxis, invasion into an endothelial cell monolayer, zebrafish and Xenopus embryonic development, mouse lung organ culture and an in vivo lung metastasis model. Two molecules, NSC305787 and NSC668394, that directly bind to ezrin with low micromolar affinity were selected based on inhibition of ezrin function in multiple assays. They inhibited ezrin phosphorylation, ezrin-actin interaction and ezrin-mediated motility of osteosarcoma (OS) cells in culture. NSC305787 mimicked the ezrin morpholino phenotype, and NSC668394 caused a unique developmental defect consistent with reduced cell motility in zebrafish. Following tail vein injection of OS cells into mice, both molecules inhibited lung metastasis of ezrin-sensitive cells, but not ezrin-resistant cells. The small molecule inhibitors NSC305787 and NSC668394 demonstrate a novel targeted therapy that directly inhibits ezrin protein as an approach to prevent tumor metastasis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|