Please use this identifier to cite or link to this item:
|Title:||A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo||Authors:||Petty, A.
MacKerell Jr., A.D.
|Issue Date:||15-Aug-2012||Citation:||Petty, A., Myshkin, E., Qin, H., Guo, H., Miao, H., Tochtrop, G.P., Hsieh, J.-T., Page, P., Liu, L., Lindner, D.J., Acharya, C., MacKerell Jr., A.D., Ficker, E., Song, J., Wang, B. (2012-08-15). A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo. PLoS ONE 7 (8) : -. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0042120||Abstract:||During tumor progression, EphA2 receptor can gain ligand-independent pro-oncogenic functions due to Akt activation and reduced ephrin-A ligand engagement. The effects can be reversed by ligand stimulation, which triggers the intrinsic tumor suppressive signaling pathways of EphA2 including inhibition of PI3/Akt and Ras/ERK pathways. These observations argue for development of small molecule agonists for EphA2 as potential tumor intervention agents. Through virtual screening and cell-based assays, we report here the identification and characterization of doxazosin as a novel small molecule agonist for EphA2 and EphA4, but not for other Eph receptors tested. NMR studies revealed extensive contacts of doxazosin with EphA2/A4, recapitulating both hydrophobic and electrostatic interactions recently found in the EphA2/ephrin-A1 complex. Clinically used as an α1-adrenoreceptor antagonist (Cardura®) for treating hypertension and benign prostate hyperplasia, doxazosin activated EphA2 independent of α1-adrenoreceptor. Similar to ephrin-A1, doxazosin inhibited Akt and ERK kinase activities in an EphA2-dependent manner. Treatment with doxazosin triggered EphA2 receptor internalization, and suppressed haptotactic and chemotactic migration of prostate cancer, breast cancer, and glioma cells. Moreover, in an orthotopic xenograft model, doxazosin reduced distal metastasis of human prostate cancer cells and prolonged survival in recipient mice. To our knowledge, doxazosin is the first small molecule agonist of a receptor tyrosine kinase that is capable of inhibiting malignant behaviors in vitro and in vivo. © 2012 Petty et al.||Source Title:||PLoS ONE||URI:||http://scholarbank.nus.edu.sg/handle/10635/99967||ISSN:||19326203||DOI:||10.1371/journal.pone.0042120|
|Appears in Collections:||Staff Publications|
Show full item record
Files in This Item:
|2012-small_molecule_agonist_EphA2_receptor-pub.pdf||3.48 MB||Adobe PDF|
checked on Mar 23, 2020
WEB OF SCIENCETM
checked on Mar 16, 2020
checked on Mar 15, 2020
checked on Mar 15, 2020
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.