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
| Autor: | Hiroshi Makino, Ken-ichirou Morishige, Eiichi Morii, Michiko Kodama, Kae Hashimoto, Yasuto Kinose, Tadashi Kimura, Takeshi Yanase, Koji Nakamura, Yoichi Yamaguchi, Akiko Itai, Seiji Mabuchi, Kenjiro Sawada, Akihito Yoshimura, Erika Nakatsuka |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Receptor complex Angiogenesis PAI-1 Focal adhesion 03 medical and health sciences chemistry.chemical_compound angiogenesis 0302 clinical medicine IMD-4482 Ovarian carcinoma Medicine biology business.industry peritoneal dissemination medicine.disease 030104 developmental biology ovarian cancer Oncology chemistry 030220 oncology & carcinogenesis Plasminogen activator inhibitor-1 biology.protein Cancer research Vitronectin business Ovarian cancer Plasminogen activator Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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 αVβ3. 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. |
| Databáze: | OpenAIRE |
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