PAI-1 leads to G1-phase cell-cycle progression through cyclin D3/cdk4/6 upregulation.
The canonical function of plasminogen activator inhibitor-1 (PAI-1/SERPINE1) is as an inhibitor of urokinase-type plasminogen activator for blood clot maintenance, but it is now also considered a pleiotropic factor that can exert diverse cellular and tumorigenic effects. However, the mechanism controlling its pleiotropic effects is far from being understood. To elucidate the tumorigenic role of PAI-1, we tested the effects of PAI-1 after manipulation of its expression or through the use of a small-molecule inhibitor, tiplaxtinin. Downregulation of PAI-1 significantly reduced cellular proliferation through an inability to progress from the G(0-G1) phase of the cell cycle. Accordingly, overexpression of PAI-1 augmented proliferation by encouraging S-phase entry. Biochemically, cell-cycle arrest was associated with the depletion of the G(1)-phase transition complexes, cyclin D3/cdk4/6 and cyclin E/cdk2, in parallel with the upregulation of the cell-cycle inhibitors p53, p21Cip1/Waf1, and p27Kip1. PAI-1 depletion significantly decreased the tumor size of urothelial T24 and UM-UC-14 xenografts, and overexpression of PAI-1 substantially increased the tumor size of HeLa xenografts. Finally, immunohistochemical analysis of human bladder and cervical tumor tissue microarrays revealed increased expression of PAI-1 in cancerous tissue, specifically in aggressive tumors, supporting the relevance of this molecule in human tumor biology.


CONCLUSIONS
Targeting PAI-1 has beneficial antitumoral effects and should be further investigated clinically.
Clinical and Translational Research, University of Hawaii Cancer Center, University of Hawaii School of Medicine, 701 Ilalo Street, Room 327, Honolulu, HI 96813. crosser@cc.hawaii.edu.
Evan Gomes
EG
Giacoia
Makito
M
Miyake
Adrienne
A
Lawton
Steve
S
Goodison
Charles J
CJ
Rosser
D000818:Animals; D059447:Cell Cycle Checkpoints / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
C534696:CCND3 protein, human; D056743:Cyclin D3; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases