Mashiko Satsuki, Kitatani Kazuyuki, Toyoshima Masafumi, Ichimura Atsuhiko, Dan Takashi, Usui Toshinori, Ishibashi Masumi, Shigeta Shogo, Nagase Satoru, Miyata Toshio, Yaegashi Nobuo
a Department of Obstetrics and Gynecology ; Tohoku University Graduate School of Medicine ; Sendai , Japan.
Cancer Biol Ther. 2015;16(2):253-60. doi: 10.1080/15384047.2014.1001271.
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.
纤溶酶原激活物抑制剂（PAI）-1可预测多种癌症的不良预后。本研究探讨了PAI-1在卵巢癌中的生物学作用及靶向药物治疗的潜力。在卵巢癌患者中，肿瘤组织中PAI-1 mRNA表达与不良预后呈正相关。为确定PAI-1在卵巢癌细胞增殖中的作用，我们检测了PAI-1抑制在表达PAI-1的卵巢癌细胞中的效果。小分子干扰RNA敲低PAI-1导致细胞生长显著受抑，并伴有G2/M期细胞周期阻滞和内源性凋亡。同样，小分子PAI-1抑制剂TM5275治疗有效阻断了高表达PAI-1的卵巢癌细胞的增殖。这些结果共同表明，PAI-1促进卵巢癌细胞生长。有趣的是，与浆液性肿瘤相比，PAI-1在卵巢透明细胞癌中的表达增加。我们的结果表明，抑制PAI-1可促进卵巢癌细胞周期阻滞和凋亡，且PAI-1抑制剂可能代表一类新型抗肿瘤药物。
