Urokinase-type plasminogen activator (uPA) is associated with
cancer recurrence where the most evidence comes from studies in
breast cancer. According to the European Organization for Research and Treatment of
Cancer, uPA is considered one of the most prominent
biomarkers for
cancer recurrence and therefore new agents are needed to inhibit it. Whether uPA is also expressed in pediatric
cancers is yet unknown. If it is then uPA inhibitors might also help children with recurrent
cancers. In this study, we addressed whether the
integrin-linked kinase inhibitor (ILK),
QLT0267, could suppress uPA. We previously showed that uPA expression is maximally inhibited when both the Akt and MAP
kinase pathways were blocked which we anticipated can be achieved via
QLT0267. In MDA-MB-231
breast cancer cells,
QLT0267 blocked signaling through Akt and MAP
kinase with a correlative decrease in uPA
protein and
mRNA, which corresponded to an inhibition of c-Jun phosphorylation. Consistent with these findings, cellular invasion was inhibited with either
QLT0267 or with
small interfering RNA against ILK. We then questioned whether uPA was commonly expressed in childhood
sarcomas and if
QLT0267 might be effective in this setting. We determined for the first time that uPA was highly expressed in
rhabdomyosarcomas (RMS), but not Ewings
sarcomas by screening cell lines (n = 31) and patient samples (n = 200) using Affymetrix microarrays. In alveolar RMS (ARMS) cell lines,
QLT0267 blocked cell signaling, uPA production, invasion and ultimately survival. We concluded that
QLT0267 blocks the production of uPA providing a new target for the management of recurrent
cancers.