Inhibition of plasminogen activator inhibitor-1 is a potential therapeutic strategy in ovarian cancer.

Abstract

Plasminogen activator inhibitor (PAI)-1 is predictive of poor outcome in several types of cancer. The present study investigated the biological role for PAI-1 in ovarian cancer and potential of targeted pharmacotherapeutics. In patients with ovarian cancer, PAI-1 mRNA expression in tumor tissues was positively correlated with poor prognosis. To determine the role of PAI-1 in cell proliferation in ovarian cancer, the effects of PAI-1 inhibition were examined in PAI-1-expressing ovarian cancer cells. PAI-1 knockdown by small interfering RNA resulted in significant suppression of cell growth accompanied with G2/M cell cycle arrest and intrinsic apoptosis. Similarly, treatment with the small molecule PAI-1 inhibitor TM5275 effectively blocked cell proliferation of ovarian cancer cells that highly express PAI-1. Together these results suggest that PAI-1 promotes cell growth in ovarian cancer. Interestingly, expression of PAI-1 was increased in ovarian clear cell carcinoma compared with that in serous tumors. Our results suggest that PAI-1 inhibition promotes cell cycle arrest and apoptosis in ovarian cancer and that PAI-1 inhibitors potentially represent a novel class of anti-tumor agents.

• Authors: Satsuki Mashiko, Kazuyuki Kitatani, Masafumi Toyoshima, Atsuhiko Ichimura, Takashi Dan, Toshinori Usui, Masumi Ishibashi, Shogo Shigeta, Satoru Nagase, Toshio Miyata, Nobuo Yaegashi
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 16 Issue 2 Pg. 253-60 ( 2015) ISSN: 1555-8576 [Electronic] United States
• PMID: 25587663 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-chloro-2-(((2-(4-(diphenylmethyl)piperazin-1-yl)-2-oxoethoxy)acetyl)amino)benzoate
• Antineoplastic Agents
• Piperazines
• Plasminogen Activator Inhibitor 1
• Plasminogen Inactivators
• RNA, Messenger
• RNA, Small Interfering
• para-Aminobenzoates

Topics

• Antineoplastic Agents (pharmacology)
• Cell Cycle (genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Immunohistochemistry
• Inhibitory Concentration 50
• Molecular Targeted Therapy
• Ovarian Neoplasms (drug therapy, genetics, metabolism, mortality, pathology)
• Piperazines (pharmacology)
• Plasminogen Activator Inhibitor 1 (genetics, metabolism)
• Plasminogen Inactivators (pharmacology)
• Prognosis
• RNA, Messenger (genetics)
• RNA, Small Interfering (genetics)
• Up-Regulation
• para-Aminobenzoates (pharmacology)