PAI-1 leads to G1-phase cell-cycle progression through cyclin D3/cdk4/6 upregulation

Evan Gomes Giacoia, Makito Miyake, Adrienne Lawton, Steven Goodison, Charles J. Rosser

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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 G0-G 1 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 G1-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.

Original languageEnglish (US)
Pages (from-to)322-334
Number of pages13
JournalMolecular Cancer Research
Volume12
Issue number3
DOIs
StatePublished - Jan 1 2014

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Cyclin D3
Plasminogen Activator Inhibitor 1
G1 Phase
Cell Cycle
Up-Regulation
Heterografts
Neoplasms
Activator Appliances
Cyclin E
Phase Transition
Urokinase-Type Plasminogen Activator
Cell Cycle Checkpoints
S Phase
Urinary Bladder Neoplasms
Thrombosis
Down-Regulation
Maintenance
Cell Proliferation

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

PAI-1 leads to G1-phase cell-cycle progression through cyclin D3/cdk4/6 upregulation. / Giacoia, Evan Gomes; Miyake, Makito; Lawton, Adrienne; Goodison, Steven; Rosser, Charles J.

In: Molecular Cancer Research, Vol. 12, No. 3, 01.01.2014, p. 322-334.

Research output: Contribution to journalArticle

Giacoia, Evan Gomes ; Miyake, Makito ; Lawton, Adrienne ; Goodison, Steven ; Rosser, Charles J. / PAI-1 leads to G1-phase cell-cycle progression through cyclin D3/cdk4/6 upregulation. In: Molecular Cancer Research. 2014 ; Vol. 12, No. 3. pp. 322-334.
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