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.
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.
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.
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
ISSN: 19326203
DOI: 10.1371/journal.pone.0042120
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
2012-small_molecule_agonist_EphA2_receptor-pub.pdf3.48 MBAdobe PDF




checked on Oct 20, 2021


checked on Oct 20, 2021

Page view(s)

checked on Oct 14, 2021


checked on Oct 14, 2021

Google ScholarTM



Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.