Department of Surgical Sciences, "Sapienza" University of Rome, 00161 Rome, Italy.
Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Monterotondo, 00015 Rome, Italy.
Int J Mol Sci. 2022 Mar 28;23(7):3724. doi: 10.3390/ijms23073724.
Increased expression of the urokinase-type plasminogen activator (uPA) system is associated with tumor invasion, neo-angiogenesis, and metastatic spread, and has been shown to positively correlate with a poor prognosis in several cancer types, including thyroid carcinomas. In recent years, several uPA inhibitors were found to have anticancer effects in preclinical studies and in some phase II clinical trials, which prompted us to evaluate uPA as a potential therapeutic target for the treatment of patients affected by the most aggressive form of thyroid cancer, the anaplastic thyroid carcinoma (ATC). In this study, we evaluated the in vitro and in vivo effects of WX-340, a highly specific and selective uPA inhibitor, on two ATC-derived cell lines, CAL-62 and BHT-101. The results obtained indicated that WX-340 was able to reduce cell adhesion and invasiveness in a dose-dependent manner in both cell lines. In addition, WX-340 increased uPA receptor (uPAR) protein levels without affecting its plasma membrane concentration. However, this compound was unable to significantly reduce ATC growth in a xenograft model, indicating that uPA inhibition alone may not have the expected therapeutic effects.
尿激酶型纤溶酶原激活物（uPA）系统的表达增加与肿瘤侵袭、新生血管形成和转移扩散有关，并已被证明与几种癌症类型的不良预后呈正相关，包括甲状腺癌。近年来，一些 uPA 抑制剂在临床前研究和一些 II 期临床试验中显示出抗癌作用，这促使我们将 uPA 作为治疗最具侵袭性甲状腺癌——间变性甲状腺癌（ATC）患者的潜在治疗靶点进行评估。在这项研究中，我们评估了高度特异性和选择性 uPA 抑制剂 WX-340 对两种源自 ATC 的细胞系 CAL-62 和 BHT-101 的体外和体内作用。结果表明，WX-340 能够以剂量依赖性方式降低两种细胞系中的细胞黏附和侵袭性。此外，WX-340 增加了 uPA 受体（uPAR）蛋白水平，而不影响其质膜浓度。然而，该化合物在异种移植模型中不能显著抑制 ATC 的生长，表明单独抑制 uPA 可能不会产生预期的治疗效果。
