Plasminogen activator inhibitor-1 is an independent prognostic factor of ovarian cancer and IMD-4482, a novel plasminogen activator inhibitor-1 inhibitor, inhibits ovarian cancer peritoneal dissemination

被引：35

作者：

Nakatsuka, Erika ^{[1
]}

Sawada, Kenjiro ^{[1
]}

Nakamura, Koji ^{[1
]}

Yoshimura, Akihito ^{[1
]}

Kinose, Yasuto ^{[1
]}

Kodama, Michiko ^{[1
]}

Hashimoto, Kae ^{[1
]}

Mabuchi, Seiji ^{[1
]}

Makino, Hiroshi ^{[2
]}

Morii, Eiichi ^{[3
]}

Yamaguchi, Yoichi ^{[4
]}

Yanase, Takeshi ^{[4
]}

Itai, Akiko ^{[4
]}

Morishige, Ken-ichirou ^{[2
]}

Kimura, Tadashi ^{[1
]}

机构：

[1] Osaka Univ, Grad Sch Med, Dept Obstet & Gynecol, Suita, Osaka, Japan

[2] Gifu Univ, Grad Sch Med, Dept Obstet & Gynecol, Gifu, Gifu, Japan

[3] Osaka Univ, Grad Sch Med, Dept Pathol, Suita, Osaka, Japan

[4] IMMD Inc, Tokyo, Japan

来源：

ONCOTARGET | 2017年 / 8卷 / 52期

关键词：

ovarian cancer; PAI-1; IMD-4482; peritoneal dissemination; angiogenesis; SOMATOMEDIN-B-DOMAIN; CELL-ADHESION; TUMOR PROGRESSION; BREAST-CANCER; UROKINASE; PAI-1; VITRONECTIN; BINDING; TYPE-1; GROWTH;

D O I：

10.18632/oncotarget.20834

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

In the present study, the therapeutic potential of targeting plasminogen activator inhibitor-1 (PAI-1) in ovarian cancer was tested. Tissues samples from 154 cases of ovarian carcinoma were immunostained with anti-PAI-1 antibody, and the prognostic value was analyzed. Among the samples, 67% (104/154) showed strong PAI-1 expression; this was significantly associated with poor prognosis (progression-free survival: 20 vs. 31 months, P = 0.0033). In particular, among patients with stage II-IV serous adenocarcinoma, PAI-1 expression was an independent prognostic factor. The effect of a novel PAI-1 inhibitor, IMD-4482, on ovarian cancer cell lines was assessed and its therapeutic potential was examined using a xenograft mouse model of ovarian cancer. IMD-4482 inhibited in vitro cell adhesion to vitronectin in PAI-1-positive ovarian cancer cells, followed by the inhibition of extracellular signal-regulated kinase and focal adhesion kinase phosphorylation through dissociation of the PAI-urokinase receptor complex from integrin aV beta 3. IMD-4482 caused G0/G1 cell arrest and inhibited the proliferation of PAI-1-positive ovarian cancer cells. In the xenograft model, IMD-4482 significantly inhibited peritoneal dissemination with the reduction of PAI-1 expression and the inhibition of focal adhesion kinase phosphorylation. Collectively, the functional inhibition of PAI-1 significantly inhibited ovarian cancer progression, and targeting PAI-1 may be a potential therapeutic strategy in ovarian cancer.

引用

页码：89887 / 89902

页数：16

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