Inhibitors of tyrosine kinase inhibit the production of urokinase plasminogen activator in human prostatic cancer cells

Abstract

Urokinase-type plasminogen activator (uPA) seems to be an important protease in prostate cancer invasion, and tyrosine phosphorylation is thought to play a role in the regulation of its production. The amount of uPA was measured with a synthetic peptide substrate after treatment with various concentrations of tyrosine kinase inhibitors (TKI). The effect on proliferation and apoptosis was also assayed. Non-toxic levels of genistein or the tyrphostin AG 490 produced up to 50% reduction of the uPA production in PC-3 and DU-145. The tyrphostins AG 1296 and AG 1478 inhibited uPA production in PC-3 cells, whereas DU-145 showed a slight increase of uPA production. TKI neither induced any detectable apoptosis, nor was there any reduction in proliferation rate. TKI can profoundly modify the production of uPA in prostatic cancer cells, thus indicating their possible use as suppressors of the invasive phenotype. The therapeutic potential of TKI warrants further investigation.

Inhibitors of Tyrosine Kinases (TKI) and Small Interfering RNAs (siRNA) are Promising Targeted Cancer Treatments

“…Recent research gives reason to hope that it may be possible to find TKIs with specific inhibitory effect on cancer cell invasion. Thus, in an in vitro invasion model using prostate cancer cells, measurement of caspase activation revealed no sign of serious cell injury at TKI doses which produced a dramatic reduction of the cells' invasive capacity [27]. This supports the notion that the observed effect is a specific interference with the invasive behaviour and not merely the result of general cytotoxicity, thus extending the well known effects of inhibition of cell proliferation and apoptosis induction caused by TKI in cultured cells [53].…”

“…In this way autophosphorylation is promoted, resulting in uncontrolled activation of growth responses [23][24][25][26]. Another important mechanism in irregular activation of TKs involves mutations that disrupt the autoregulation of the kinase [27]. Finally, increased TK activity may be due to a decrease of factors that limit TK activity, such as tyrosine phosphatases or other TK inhibitory proteins [28].…”

Mechanisms of action of novel agents for prostate cancer chemoprevention

“…Genistein is reported to inhibit uPA production in PC3 cells (Skogseth et al 2005). Retinoic acid inhibits the malignant potential, including extracellular proteolysis of PCa by inhibiting uPA expression (Webber & R P Singh and R Agarwal: PCa chemoprevention www.endocrinology-journals.org Waghray 1995).…”

The invasive behaviour of prostatic cancer cells is suppressed by inhibitors of tyrosine kinase

“…Receptor tyrosine kinases, which phosphorylate specific tyrosine residues on a small set of intracellular signalling proteins, include important receptors in the transduction of growth stimuli, for example, epidermal growth factor receptor (EGFR) (19). In the present study we examined the cells' invasive ability after treatment with two TKI, which we have previously reported to produce an overall reduction in the expression of uPA (10). Using this system we confirmed a crucial role of plasminogen in the migration process.…”