An anti-urokinase plasminogen activator receptor antibody (ATN-658) blocks prostate cancer invasion, migration, growth, and experimental skeletal metastasis in vitro and in vivo

Neoplasia. 2010 Oct;12(10):778-88. doi: 10.1593/neo.10296.


Urokinase plasminogen activator receptor (uPAR) is a multidomain protein that plays important roles in the growth, invasion, and metastasis of a number of cancers. In the present study, we examined the effects of administration of a monoclonal anti-uPAR antibody (ATN-658) on prostate cancer progression in vitro and in vivo. We examined the effect of treatment of ATN-658 on human prostate cancer cell invasion, migration, proliferation, and regulation of intracellular signaling pathways. For in vivo studies, PC-3 cells (1 x 10(6)) were inoculated into the right flank of male Balb C nu/nu mice through subcutaneous or through intratibial route (2 x 10(5)) of male Fox Chase severe combined immunodeficient mice to monitor the effect on tumor growth and skeletal metastasis. Treatment with ATN-658 resulted in a significant dose-dependent decrease in PC-3 cell invasion and migration without affecting cell doubling time. Western blot analysis showed that ATN-658 treatment decreased the phosphorylation of serine/threonine protein kinase B (AKT), mitogen-activated protein kinase (MAPK), and focal adhesion kinase (FAK) without affecting AKT, MAPK, and FAK total protein expression. In in vivo studies, ATN-658 caused a significant decrease in tumor volume and a marked reduction in skeletal lesions as determined by Faxitron x-ray and micro-computed tomography. Immunohistochemical analysis of subcutaneous and tibial tumors showed a marked decrease in the levels of expression of pAKT, pMAPK, and pFAK, consistent with the in vitro observations. Results from these studies provide compelling evidence for the continued development of ATN-658 as a potential therapeutic agent for the treatment of prostate and other cancers expressing uPAR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Blotting, Western
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / immunology
  • Bone Neoplasms / secondary
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects*
  • Humans
  • Immunoenzyme Techniques
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / pathology
  • Receptors, Urokinase Plasminogen Activator / antagonists & inhibitors*
  • Receptors, Urokinase Plasminogen Activator / immunology
  • Receptors, Urokinase Plasminogen Activator / metabolism
  • Signal Transduction / radiation effects
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • ATN-658
  • Antibodies, Monoclonal
  • Receptors, Urokinase Plasminogen Activator