| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Papers In Press, published online ahead of print August 26, 2005
Department of Biomedical and Therapeutic Sciences and Department of Neurosurgery, University of Illinois, College of Medicine at Peoria, Peoria, IL 61656
Corresponding Author: jsrao{at}uic.edu
SUMMARY The invasive ability of tumor cells plays a key role in prostate cancer metastasis and is a major cause of treatment failure. Urokinase plasminogen activator (uPA) and its receptor (uPAR)-mediated signaling have been implicated in tumor cell invasion, survival and metastasis in a variety of cancers. This study was undertaken to investigate the biological roles of uPA and uPAR in prostate cancer cell invasion, survival and the potential of uPA and uPAR as targets for prostate cancer therapy. In this study we utilized small hairpin RNAs (shRNAs), also referred to as small interfering RNAs (siRNAs), to target human uPA and uPAR. These siRNA constructs significantly inhibited uPA and uPAR expression at both the mRNA and protein levels in the highly metastatic prostate cancer cell line PC3. Furthermore, simultaneous silencing of the genes for uPA and uPAR using a single plasmid construct expressing shRNAs for both uPA and uPAR significantly reduced cell viability and ultimately resulted in the induction of apoptotic cell death. RNAi for uPA and uPAR also abrogated uPA-uPAR signaling to downstream target molecules such as extracellular-signal regulated kinases 1/2 (ERK1/2) and the signal transducer and activator of transcription 3 (Stat 3). In addition, our results demonstrate that intratumoral injection with the plasmid construct expressing shRNAs for uPA and uPAR almost completely inhibited established tumor growth and survival in an orthotopic mouse prostate cancer model. These findings uncovered evidence of a complex signaling network operating downstream of uPA-uPAR that actively advances tumor cell invasion, proliferation and survival of prostate cancer cells. Thus, RNAi-directed targeting of uPA and uPAR is a convenient and novel tool for studying the biological role of the uPA-uPAR system and raises the potential of its application for prostate cancer therapy.
J. Biol. Chem, 10.1074/jbc.M503111200
Submitted on March 21, 2005
Revised on August 3, 2005
Accepted on August 26, 2005
RNA interference-directed knockdown of urokinase plasminogen activator and urokinase plasminogen activator receptor inhibits prostate cancer cell invasion, survival and tumorigenicity in vivo
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Abdulghani, L. Gu, A. Dagvadorj, J. Lutz, B. Leiby, G. Bonuccelli, M. P. Lisanti, T. Zellweger, K. Alanen, T. Mirtti, et al. Stat3 Promotes Metastatic Progression of Prostate Cancer Am. J. Pathol., June 1, 2008; 172(6): 1717 - 1728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. K. Pulukuri, B. Gorantla, and J. S. Rao Inhibition of Histone Deacetylase Activity Promotes Invasion of Human Cancer Cells through Activation of Urokinase Plasminogen Activator J. Biol. Chem., December 7, 2007; 282(49): 35594 - 35603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Du, H. Leung, K.M. F. Khan, C. G. Miller, K. Subbaramaiah, D. J. Falcone, and A. J. Dannenberg Tobacco Smoke Induces Urokinase-Type Plasminogen Activator and Cell Invasiveness: Evidence for an Epidermal Growth Factor Receptor Dependent Mechanism Cancer Res., September 15, 2007; 67(18): 8966 - 8972. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. K. Pulukuri and J. S. Rao Small Interfering RNA Directed Reversal of Urokinase Plasminogen Activator Demethylation Inhibits Prostate Tumor Growth and Metastasis Cancer Res., July 15, 2007; 67(14): 6637 - 6646. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Kohno, N. Takahashi, T. Shinohara, T. Ooie, K. Yufu, M. Nakagawa, H. Yonemochi, M. Hara, T. Saikawa, and H. Yoshimatsu Receptor-Mediated Suppression of Cardiac Heat-Shock Protein 72 Expression by Testosterone in Male Rat Heart Endocrinology, July 1, 2007; 148(7): 3148 - 3155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Kong, Y. Li, Z. Wang, S. Banerjee, and F. H. Sarkar Inhibition of Angiogenesis and Invasion by 3,3'-Diindolylmethane Is Mediated by the Nuclear Factor-{kappa}B Downstream Target Genes MMP-9 and uPA that Regulated Bioavailability of Vascular Endothelial Growth Factor in Prostate Cancer Cancer Res., April 1, 2007; 67(7): 3310 - 3319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Li, C. S. Gondi, D. H. Dinh, W. C. Olivero, M. Gujrati, and J. S. Rao Transfection with Anti-p65 Intrabody Suppresses Invasion and Angiogenesis in Glioma Cells by Blocking Nuclear Factor-{kappa}B Transcriptional Activity Clin. Cancer Res., April 1, 2007; 13(7): 2178 - 2190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. K. Pulukuri, N. Estes, J. Patel, and J. S. Rao Demethylation-Linked Activation of Urokinase Plasminogen Activator Is Involved in Progression of Prostate Cancer Cancer Res., February 1, 2007; 67(3): 930 - 939. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-S. Annicotte, I. Iankova, S. Miard, V. Fritz, D. Sarruf, A. Abella, M.-L. Berthe, D. Noel, A. Pillon, F. Iborra, et al. Peroxisome Proliferator-Activated Receptor {gamma} Regulates E-Cadherin Expression and Inhibits Growth and Invasion of Prostate Cancer. Mol. Cell. Biol., October 1, 2006; 26(20): 7561 - 7574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. P Singh and R. Agarwal Mechanisms of action of novel agents for prostate cancer chemoprevention. Endocr. Relat. Cancer, September 1, 2006; 13(3): 751 - 778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Gardsvoll, B. Gilquin, M. H. Le Du, A. Menez, T. J. D. Jorgensen, and M. Ploug Characterization of the Functional Epitope on the Urokinase Receptor: COMPLETE ALANINE SCANNING MUTAGENESIS SUPPLEMENTED BY CHEMICAL CROSS-LINKING J. Biol. Chem., July 14, 2006; 281(28): 19260 - 19272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Alfano, I. Iaccarino, and M. P. Stoppelli Urokinase Signaling through Its Receptor Protects against Anoikis by Increasing BCL-xL Expression Levels J. Biol. Chem., June 30, 2006; 281(26): 17758 - 17767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Madsen, E. I. Deryugina, S. Niessen, B. F. Cravatt, and J. P. Quigley Activity-based Protein Profiling Implicates Urokinase Activation as a Key Step in Human Fibrosarcoma Intravasation J. Biol. Chem., June 9, 2006; 281(23): 15997 - 16005. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
