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.

Plasminogen Activator Inhibitor-1 in Cancer: Rationale and Insight for Future Therapeutic Testing

“…The oral administration of PAI-039 to mice xenotransplanted with human T24 bladder and HeLa cervical cancer cells resulted in a 2-fold reduction of tumor volume after 14 days associated with a decrease in tumor cell proliferation and vascularization and an increase in apoptosis (52). The TM5275 inhibitor was recently shown to increase apoptosis in vitro in ovarian cancer cell lines (53). The in vivo activity of these inhibitors in cancer models have not been reported with the exception of TM5275 and TM5441 in a most recent study (54).…”

WOMEN IN CANCER THEMATIC REVIEW: Ovarian cancer–peritoneal cell interactions promote extracellular matrix processing

“…The effect of PAI-1 on tumour growth is likely to be dependent on its abundance (McMahon et al 2001), but it appears that PAI-1 also has functions which are independent of the of plasminogen-plasmin system (Czekay & Loskutoff 2009). PAI-1 knockdown resulted in reduced growth and increased apoptosis of ovarian cancer cell lines, and a small molecule inhibitor of PAI-1 (TM5275) blocked the proliferation of ovarian cancer cells with high PAI-1 expression (Mashiko et al 2015).…”

“…As PAI-1 inhibits plasmin generation, it would be expected to be reduced in cancers; however surprisingly, PAI-1 is increased in most cancers including ovarian cancer and increased levels of both PAI-1 and u-PA are associated with reduced ovarian cancer survival (Kuhn et al 1994, Konecny et al 2001, Mashiko et al 2015. To date, the molecular mechanism of this paradox has not been explained (Didiasova et al 2014) and may be due the incomplete understanding of the complex plasminogen-plasmin system and its interactions with other factors in tumours (Kwaan et al 2013).…”

“…Targeting PAI-1 in the peritoneal microenvironment is a promising approach to inhibit ovarian cancer metastasis but needs further evaluation. To date, the small molecule inhibitor of PAI-1 (TM5275) has only been tested on ovarian cancer cells in vitro (Mashiko et al 2015).…”

Bilateral ovarian carcinomas differ in the expression of metastasis-related genes

“…Both genes belong to the same gene family, encode proteins that participate in the regulation of fibrinolysis and have been linked to cancer and metastasis (23). SERPINE1 has been proposed to have a pro-tumorigenic function by protecting tumor cells from apoptosis, since inhibition of SERPINE1 has been demonstrated to increase spontaneous apoptosis in cancer cell lines (25,26). High expression of SERPINE1 is associated with poor outcome in several cancer types, including ovarian (27), gastric (28), colorectal (29), renal (30) and breast (31) cancer.…”