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Cleaved high-molecular-weight kininogen and its domain 5 inhibit migration and invasion of human prostate cancer cells through the epidermal growth factor receptor pathway

Oncogene volume 28, pages 2756–2765 (2009)Cite this article

Abstract

Upregulation and activation of epidermal growth factor receptor and/or urokinase-type plasminogen activator receptor in a variety of cancers have been shown to be associated with poor prognosis. High-molecular-weight kininogen can be hydrolysed by plasma kallikrein to bradykinin and cleaved high-molecular-weight kininogen (HKa). HKa and its domain 5 (D5) both have been shown to have potent anti-angiogenic activity. We now show that HKa blocks human prostate cancer cell (DU145) migration by 76.0±2.4% at 300 nM and invasion by 78.0±12.9% at 11.1 nM. D5 inhibits tumor migration and invasion in a concentration-dependent manner. Stimulation by basic fibroblast growth factor (bFGF) or vascular endothelial growth factor results in clustering of urokinase-type plasminogen activator receptor (uPAR) and epidermal growth factor receptor (EGFR) on the surface of DU145 cells. The co-localization of uPAR and EGFR is prevented by HKa. Immunoprecipitation suggests that uPAR, EGFR and α5β1 integrin formed a ternary complex. Immunoblotting shows that HKa significantly decreases the bFGF-transactivated phosphorylation of EGFR at Tyr 1173 between 30 min and 4 h. The phosphorylation of extracellular signal-regulated kinase (ERK) and AKT, which are downstream effectors of EGFR, is also inhibited by HKa. These novel data indicate that HKa and D5 inhibit migration and invasion of human prostate cancer cells through an EGFR/uPAR pathway, suggesting the therapeutic potential of HKa and D5 to decrease metastasis of human prostate cancer.

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Abbreviations

EGFR:

epidermal growth factor receptor

HK:

high-molecular-weight kininogen

HKa:

cleaved high-molecular-weight kininogen

uPA:

urokinase-type plasminogen activator

uPAR:

urokinase-type plasminogen activator receptor

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Acknowledgements

This study was supported by National Institutes of Health Grants R01 CA83121, R01 AR051713 and T32 HL07777 to RW Colman.

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Authors and Affiliations

  1. The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, USA

    Y Liu, R Pixley, M Fusaro, G Godoy, E Kim, M E Bromberg & R W Colman

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  1. Y Liu
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  2. R Pixley
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  3. M Fusaro
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  4. G Godoy
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  5. E Kim
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  6. M E Bromberg
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  7. R W Colman
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Correspondence to Y Liu.

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Liu, Y., Pixley, R., Fusaro, M. et al. Cleaved high-molecular-weight kininogen and its domain 5 inhibit migration and invasion of human prostate cancer cells through the epidermal growth factor receptor pathway. Oncogene 28, 2756–2765 (2009). https://doi.org/10.1038/onc.2009.132

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