title: 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.affiliation: a Department of Obstetrics and Gynecology ; Tohoku University Graduate School of Medicine ; Sendai , Japan.
authors.forename: Satsuki
authors.initials: S
authors.lastname: Mashiko
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kitatani
authors.forename: Masafumi
authors.initials: M
authors.lastname: Toyoshima
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Ichimura
authors.forename: Takashi
authors.initials: T
authors.lastname: Dan
authors.forename: Toshinori
authors.initials: T
authors.lastname: Usui
authors.forename: Masumi
authors.initials: M
authors.lastname: Ishibashi
authors.forename: Shogo
authors.initials: S
authors.lastname: Shigeta
authors.forename: Satoru
authors.initials: S
authors.lastname: Nagase
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.forename: Nobuo
authors.initials: N
authors.lastname: Yaegashi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D015849:Plasminogen Inactivators / Q000494:pharmacology*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015854:Up-Regulation; D062366:para-Aminobenzoates / Q000494:pharmacology
chemical_list: C549556:5-chloro-2-(((2-(4-(diphenylmethyl)piperazin-1-yl)-2-oxoethoxy)acetyl)amino)benzoate; D000970:Antineoplastic Agents; D010879:Piperazines; D017395:Plasminogen Activator Inhibitor 1; D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D062366:para-Aminobenzoates
keywords: PAI-1, plasminogen activator inhibitor-1; PARP, poly (ADP-ribose) polymerase; PI, propidium iodide; TM5275; cancer therapeutics; clear cell carcinoma of the ovary; ovarian cancer; plasminogen activator inhibitor-1; plasminogen activator inhibitor-1 inhibitor; siRNA, small interfering RNA; uPA, urokinase-type plasminogen activator