and suppress the activation of pro uPA and signaling pathways initiated by uPA, which underscore its potential in prevention of tumor metastasis. The metastatic CP-466722 ATM inhibitor spread of cancer cells is a dreaded complication of malignant neoplasms. Metastasis is a multistep process in which malignant cells must initially migrate from the primary tumor, invade the surrounding tissue, and enter the vascular circulation. If they are able to survive in the blood stream, they must then successfully arrest at a secondary target site, cross the vascular barrier, and migrate into the extravascular connective tissues. Subsequently, tumor cells may proliferate to form a clinically relevant metastatic colony. In the fig. 1 and fig.
2, we showed that HKa and D5 both inhibited cell migration and invasion of prostate cancer cells in a dose dependent CYC116 VEGFR inhibitor manner, which strongly indicated the potential of HKa and D5 to prevent the metastasis of prostate cancer cells since cell migration and invasion are initial steps of tumor metastasis. In this study, we first compared the inhibitory potency of HKa and D5 on tumor cell motility and invasion. We found that both HKa and D5 were potent inhibitors of tumor cell invasion, since they at 11.1 nM inhibited tumor invasion about 90%. As shown in fig. 1, the inhibitory Liu et al. Page 7 Oncogene. Author manuscript, available in PMC 2010 April 28. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript effect of HKa on tumor migration is more potent than that of D5 but both significantly slowed down the tumor motility.
HKa and D5 mimicked the inhibitory effects of AG 1478 on tumor motility and invasion, indicating HKa and D5 are alternative EGFR inhibitors. The molecular mechanism of HKa and D5 for exerting its inhibitory effects on tumor motility and invasion is that both HKa and D5 can bind to uPAR and block the association of uPAR and EGFR. This observation was verified by both immunofluorescence and immunoprecipitation experiments. Thus, our data revealed the potential of HKa and D5 on the inhibition of prostate cancer metastasis. Abbreviations CaP carcinoma of the prostate HK high molecular weight kininogen HKa cleaved high molecular weight kininogen EGFR epidermal growth factor receptor uPA urokinase type plasminogen activator uPAR urokinase type plasminogen activator receptor.
Acknowledgments This work was supported by National Institutes of Health grants R01 CA83121, R01 AR051713 and T32 HL07777 to R.W. Colman. INTRODUCTION Epidermal growth factor plays a number of key roles in the kidney, contributing to cellular proliferative and survival pathways, renal metabolism, regenerative hyperplasia, tubulointerstitial injury, tubulogenesis, transport, renal cyst formation and renal development. EGF also has been implicated in the genesis and development of polycystic kidney disease. Despite the importance of EGF in many renal functions, particularly in renal tubules and mesangial cells, little is known about its effects in glomerular podocytes. Podocytes are critical for the maintenance of normal glomerular structure, and aberrant podocyte function has been implicated in the pathogenesis of chronic renal diseases. These highly specialized cells are characterized by the formation of foot processes that are interconnected by the slit diaphragm, which is a critical component of the glomerular filtration barrier. Pod