A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo

PLoS ONE

Volumn 7, Issue 8, 2012, Pages

  Petty, Aaron ^a   Myshkin, Eugene ^a   Qin, Haina ^b   Guo, Hong ^a   Miao, Hui ^a   Tochtrop, Gregory P ^a,c   Hsieh, Jer Tsong ^d   Page, Phillip ^e   Liu, Lili ^a   Lindner, Daniel J ^f   Acharya, Chayan ^g   MacKerell, Alexander D ^g   Ficker, Eckhard ^a   Song, Jianxing ^b,h   Wang, Bingcheng ^a  

^a CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^c CASE WESTERN RESERVE UNIVERSITY   (United States)

^d UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^e Reichert Inc ^*  (United States)

^f TAUSSIG CANCER INSTITUTE   (United States)

^g UNIVERSITY OF MARYLAND SCHOOL OF PHARMACY   (United States)

^h NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA 1 ADRENERGIC RECEPTOR; DOXAZOSIN; EPHRIN RECEPTOR A2; EPHRIN RECEPTOR A4; MITOGEN ACTIVATED PROTEIN KINASE; PROTEIN KINASE B;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER INHIBITION; CANCER SURVIVAL; CELL MIGRATION; CONTROLLED STUDY; DISTANT METASTASIS; DRUG PROTEIN BINDING; ENZYME ACTIVITY; ENZYME INHIBITION; HYDROPHOBICITY; IN VITRO STUDY; IN VIVO STUDY; INTERNALIZATION; LUNG METASTASIS; MALE; METASTASIS; METASTASIS INHIBITION; MIGRATION INHIBITION; MITOSIS INHIBITION; MOUSE; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; OVERALL SURVIVAL; PROSTATE CANCER; PROTEIN PROTEIN INTERACTION; STATIC ELECTRICITY;

EID: 84865050506     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0042120     Document Type: Article

References (61)

1. Lindberg RA, Hunter T, (1990) cDNA cloning and characterization of eck, an epithelial cell receptor protein-tyrosine kinase in the eph/elk family of protein kinases. Mol Cell Biol 10: 6316-6324.
2. Ireton RC, Chen J, (2005) EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics. Curr Cancer Drug Targets 5: 149-157.
3. Pasquale EB, (2010) Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer 10: 165-180.
4. Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE, (2004) EphA2: a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma. Oncogene 23: 1448-1456.
5. Miao H, Wang B, (2009) Eph/ephrin signaling in epithelial development and homeostasis. Int J Biochem Cell Biol 41: 762-770.
6. Thaker PH, Deavers M, Celestino J, Thornton A, Fletcher MS, et al. (2004) EphA2 expression is associated with aggressive features in ovarian carcinoma. Clin Cancer Res 10: 5145-5150.
7. Wang B, (2011) Cancer cells exploit the eph-ephrin system to promote invasion and metastasis: tales of unwitting partners. Sci Signal 4: e28.
8. Zelinski DP, Zantek ND, Stewart JC, Irizarry AR, Kinch MS, (2001) EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res 61: 2301-2306.
9. Miao H, Li D-Q, Mukherjee A, Guo H, Petty A, et al. (2009) EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell 16: 9-20.
10. Astin JW, Batson J, Kadir S, Charlet J, Persad RA, et al. (2010) Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells. Nat Cell Biol 12: 1194-1204.
11. Dohn M, Jiang J, Chen X, (2001) Receptor tyrosine kinase EphA2 is regulated by p53-family proteins and induces apoptosis. Oncogene 20: 6503-6515.
12. Miao H, Wei BR, Peehl DM, Li Q, Alexandrou T, et al. (2001) Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nat Cell Biol 3: 527-530.
13. Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE, (2004) Ligation of EphA2 by Ephrin A1-Fc inhibits pancreatic adenocarcinoma cellular invasiveness. Biochem Biophys Res Commun 320: 1096-1102.
14. Noblitt LW, Bangari DS, Shukla S, Knapp DW, Mohammed S, et al. (2004) Decreased tumorigenic potential of EphA2-overexpressing breast cancer cells following treatment with adenoviral vectors that express EphrinA1. Cancer Gene Ther 11: 757-766.
15. Guo H, Miao H, Gerber L, Singh J, Denning MF, et al. (2006) Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin. Cancer Res 66: 7050-7058.
16. Miao H, Wang B, (2012) EphA receptor signaling-complexity and emerging themes. Semin Cell Dev Biol 23: 16-25.
17. Pasquale EB, (2005) Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol Cell Biol 6: 462-475.
18. Wilkinson DG, (2001) Multiple roles of EPH receptors and ephrins in neural development. Nat Rev Neurosci 2: 155-164.
19. Yang NY, Fernandez C, Richter M, Xiao Z, Valencia F, et al. (2011) Crosstalk of the EphA2 receptor with a serine/threonine phosphatase suppresses the Akt-mTORC1 pathway in cancer cells. Cell Signal 23: 201-212.
20. Macrae M, Neve RM, Rodriguez-Viciana P, Haqq C, Yeh J, et al. (2005) A conditional feedback loop regulates Ras activity through EphA2. Cancer Cell 8: 111-118.
21. Wykosky J, Gibo DM, Stanton C, Debinski W, (2005) EphA2 as a novel molecular marker and target in glioblastoma multiforme. Mol Cancer Res 3: 541-551.
22. Himanen JP, Rajashankar KR, Lackmann M, Cowan CA, Henkemeyer M, et al. (2001) Crystal structure of an Eph receptor-ephrin complex. Nature 414: 933-938.
23. Myshkin E, Wang B, (2003) Chemometrical classification of Ephrin ligands and Eph kinases using GRID/CPCA approach. J Chem Inf Comput Sci 43: 1004-1010.
24. Himanen JP, Goldgur Y, Miao H, Myshkin E, Guo H, et al. (2009) Ligand recognition by A-class Eph receptors: crystal structures of the EphA2 ligand-binding domain and the EphA2/ephrin-A1 complex. EMBO Rep 10: 722-728.
25. Lipinski CA, (2007) Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 44: 235-249.
26. Ewing TJ, Makino S, Skillman AG, Kuntz ID, (2001) DOCK 4.0: search strategies for automated molecular docking of flexible molecule databases. J Comput Aided Mol Des 15: 411-428.
27. Miao H, Strebhardt K, Pasquale EB, Shen TL, Guan JL, et al. (2005) Inhibition of integrin-mediated cell adhesion but not directional cell migration requires catalytic activity of EphB3 receptor tyrosine kinase: Role of Rho family small GTPases. J Biol Chem 280: 923-932.
28. Constantine JW, Lebel W, (1980) Complete blockade by phenoxybenzamine of α1- but not of α2- vascular receptors in dogs and the effects of propranolol. Naunyn-Schmiedeberg's Arch Pharmacol 314: 149-156.
29. Nickerson M, (1962) Mechanism of the prolonged adrenergic blockade by haloalkylamines. Arch Int Pharmacodyn Ther 140: 237-250.
30. Smyth DD, Umemura S, Pettinger WA, (1984) Alpha-1 adrenoceptor selectivity of phenoxybenzamine in the rat kidney. J Pharmacol Exp Ther 230: 387-392.
31. Hui H, Fernando MA, Heaney AP, (2008) The alpha1-adrenergic receptor antagonist doxazosin inhibits EGFR and NF-kappaB signalling to induce breast cancer cell apoptosis. Eur J Cancer 44: 160-166.
32. Miao H, Burnett E, Kinch M, Simon E, Wang B, (2000) Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol 2: 62-69.
33. Kyprianou N, Benning CM, (2000) Suppression of human prostate cancer cell growth by alpha1-adrenoceptor antagonists doxazosin and terazosin via induction of apoptosis. Cancer Res 60: 4550-4555.
34. Eph Nomenclature Committee (1997) Unified nomenclature for Eph family receptors and their ligands, the ephrins. Eph Nomenclature Committee [letter] [In Process Citation]. Cell 90: 403-404.
35. Qin H, Shi J, Noberini R, Pasquale EB, Song J, (2008) Crystal structure and NMR binding reveal that two small molecule antagonists target the high affinity Ephrin-binding channel of the EphA4 receptor. J Biol Chem 283: 29473-29484.
36. Karplus M, Kuriyan J, (2005) Molecular dynamics and protein function. Proc Natl Acad Sci U S A 102: 6679-6685.
37. Popovych N, Sun S, Ebright RH, Kalodimos CG, (2006) Dynamically driven protein allostery. Nat Struct Mol Biol 13: 831-838.
38. Shi J, Han N, Lim L, Lua S, Sivaraman J, et al. (2011) Dynamically-driven inactivation of the catalytic machinery of the SARS 3C-like protease by the N214A mutation on the extra domain. PLoS Comput Biol 7: e1001084.
39. Smock RG, Gierasch LM, (2009) Sending Signals Dynamically. Science 324: 198-203.
40. Fushman D, Cahill S, Cowburn D, (1997) The main-chain dynamics of the dynamin pleckstrin homology (PH) domain in solution: analysis of 15N relaxation with monomer/dimer equilibration. J Mol Biol 266: 173-194.
41. Hall JB, Fushman D, (2003) Characterization of the overall and local dynamics of a protein with intermediate rotational anisotropy: Differentiating between conformational exchange and anisotropic diffusion in the B3 domain of protein G. J Biomol NMR 27: 261-275.
42. Walker O, Varadan R, Fushman D, (2004) Efficient and accurate determination of the overall rotational diffusion tensor of a molecule from 15N relaxation data using computer program ROTDIF. J Magn Reson 168: 336-345.
43. Menges CW, McCance DJ, (2008) Constitutive activation of the Raf-MAPK pathway causes negative feedback inhibition of Ras-PI3K-AKT and cellular arrest through the EphA2 receptor. Oncogene 27: 2934-2940.
44. Walker-Daniels J, Riese DJ, Kinch MS, (2002) c-Cbl-dependent EphA2 protein degradation is induced by ligand binding. Mol Cancer Res 1: 79-87.
45. Xie D, Gore C, Zhou J, Pong RC, Zhang H, et al. (2009) DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis. Proc Natl Acad Sci U S A 106: 19878-19883.
46. Xie D, Gore C, Liu J, Pong RC, Mason R, et al. (2010) Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis. Proc Natl Acad Sci U S A 107: 2485-2490.
47. Pienta KJ, Abate-Shen C, Agus DB, Attar RM, Chung LW, et al. (2008) The current state of preclinical prostate cancer animal models. Prostate 68: 629-639.
48. Yang G, Timme TL, Park SH, Wu X, Wyllie MG, et al. (1997) Transforming growth factor beta 1 transduced mouse prostate reconstitutions: II. Induction of apoptosis by doxazosin. Prostate 33: 157-163.
49. Benning CM, Kyprianou N, (2002) Quinazoline-derived alpha1-adrenoceptor antagonists induce prostate cancer cell apoptosis via an alpha1-adrenoceptor-independent action. Cancer Res 62: 597-602.
50. Alaimo PJ, Shogren-Knaak MA, Shokat KM, (2001) Chemical genetic approaches for the elucidation of signaling pathways. Curr Opin Chem Biol 5: 360-367.
51. Hezel AF, Bardeesy N, (2008) LKB1; linking cell structure and tumor suppression. Oncogene 27: 6908-6919.
52. Visser S, Yang X, (2010) LATS tumor suppressor: a new governor of cellular homeostasis. Cell Cycle 9: 3892-3903.
53. Carvalho RF, Beutler M, Marler KJ, Knoll B, Becker-Barroso E, et al. (2006) Silencing of EphA3 through a cis interaction with ephrinA5. Nat Neurosci 9: 322-330.
54. Wang BC, (2008) PTPases: "Eph" ective arbitrators of attraction. Blood 112: 455-456.
55. Chrencik JE, Brooun A, Kraus ML, Recht MI, Kolatkar AR, et al. (2006) Structural and biophysical characterization of the EphB4-+EphrinB2 protein-protein interaction and receptor specificity. J Biol Chem 281: 28185-28192.
56. Himanen JP, Nikolov DB, (2002) Purification, crystallization and preliminary characterization of an Eph-B2/ephrin-B2 complex. Acta Crystallogr D Biol Crystallogr 58: 533-535.
57. Himanen JP, Chumley MJ, Lackmann M, Li C, Barton WA, et al. (2004) Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nat Neurosci 7: 501-509.
58. Noberini R, Koolpe M, Peddibhotla S, Dahl R, Su Y, et al. (2008) Small molecules can selectively inhibit ephrin binding to the EphA4 and EphA2 receptors. J Biol Chem 283: 29461-29472.
59. Kuntz ID, Blaney JM, Oatley SJ, Langridge R, Ferrin TE, (1982) A geometric approach to macromolecule-ligand interactions. J Mol Biol 161: 269-288.
60. Connolly ML, (1983) Solvent-accessible surfaces of proteins and nucleic acids. Science 221: 709-713.
61. Weiner SJ, Kollman PA, Case DA, Singh UC, Ghio C, et al. (1984) A new force field for molecular mechanical simulation of nucleic acids and proteins. J Am Chem Soc 106: 765-784.