Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV-3 ovarian cancer cells.
OBJECTIVE
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.
Whitley
Brandi R
BR
Department of Pathology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7035, USA.
Beaulieu
Lea M
LM
Carter
Jennifer C
JC
Church
Frank C
FC
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D005260:Female; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*
D002867:Chromones; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D014568:Urokinase-Type Plasminogen Activator; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one