Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV-3 ovarian cancer cells

Abstract

Objectives-Increased levels of urokinase-type plasminogen activator (uPA) are associated with shortened overall survival in ovarian cancer patients. Additionally, elevated levels of the serine protease inhibitor (serpin), plasminogen activator inhibitor-1 (PAI-1), a uPA inhibitor, have also been correlated with an unfavorable prognosis in ovarian cancer. Therefore, it is critical to understand the signaling pathways that regulate PAI-1 and uPA expression in cancer cell migration-invasion.Methods-We studied the PI3K/Akt, Rho kinase/ROCK, p38 MAPK and MEK pathways and their modulation of PAI-1 and uPA expression and wound-induced cell migration in SKOV-3 ovarian cancer cells. The PI3K/Akt pathway was further examined using pharmacological inhibitors (LY294002 and wortmannin), Akt siRNA, constitutively active Akt adenovirus and treatment with IGF-1/insulin in the SKOV-3 cells.Results-The PI3K/Akt pathway negatively regulates PAI-1 expression and positively correlates with migratory abilities and uPA expression in SKOV-3 cells. A reduction in active Akt results in an increase in PAI-1 expression coupled with a decrease in uPA expression to ultimately result in reduced cell migration and invasion. By contrast, an increase in Akt activity reduces PAI-1 expression and results in an increase in SKOV-3 wound-induced cell migration. Furthermore, IGF-1 and insulin stimulated SKOV-3 migration by altering the balance between uPA and PAI-1 to favor uPA, and the enhanced migration was attenuated by treatment with LY294002 indicating PI3K/Akt in this pathway. Conclusions-These results suggest an overall ovarian tumor-protective role for PAI-1, and that the PI3K/Akt signaling pathway regulates the ratio of PAI-1:uPA to either increase or decrease cell migration.

Activated platelets increase fibrinolysis of mesenchymal progenitor cells

“…These findings together with those of others support the importance of JNK and PI3K/AKT signaling for the regulation of plasminogen activation. 31,34,40 The incomplete inhibition of plasminogen activation by SP600125 and LY294002, however, suggests that other pathways may be involved in the regulation of plasminogen activation.…”

PI3K pathway inhibitor LY294002 alters Jurkat T cell biobehaviours via ERK1/2-ICBP90 mediation

“…LY294002 is shown to exert anti-tumorigenic effect in vivo and in vitro by the induction of apoptosis and cell growth arrest [8,9]. Moreover, tumour cell invasion and migration could be significantly attenuated by LY294002 treatment in several tumour models [10,11]. Until now, most studies on LY294002 attribute its anti-cancer activity to the inhibition of the PI3K pathway [6].…”

Modulation of urokinase plasminogen activator system by poly(ADP-ribose)polymerase-1 inhibition

“…Several signaling pathways, like MAP kinases, phosphoinositide 3-kinase (PI3 K) survival pathways, Wnt, p53, etc. have different regulation patterns depending on the cell type (Whitley et al 2007;He et al 2010;Moreau et al 2011). In our experiments we show that inhibition of several signaling pathways modulates uPA activity.…”