College of Pharmacy, Nankai University, 300350, Tianjin, People's Republic of China.
State Key Laboratory of Medicinal Chemical Biology, Nankai University, 300350, Tianjin, People's Republic of China.
Cell Death Dis. 2019 Oct 7;10(10):757. doi: 10.1038/s41419-019-1986-2.
PAI-1 plays significant roles in cancer occurrence, relapse and multidrug resistance and is highly expressed in tumours. ACT001, which is currently in phase I clinical trials for the treatment of glioblastoma (GBM). However, the detailed molecular mechanism of ACT001 is still unclear. In this study, we investigated the effects of ACT001 on glioma cell proliferation and clarified its mechanism. We discovered that PAI-1 was the direct target of ACT001 by a cellular thermal shift assay. Then, the interaction between ACT001 and PAI-1 was verified by Biacore assays, thermal stability assays and ACT001 probe assays. Furthermore, from the proteomic analysis, we found that ACT001 directly binds PAI-1 to inhibit the PI3K/AKT pathway, which induces the inhibition of glioma cell proliferation, invasion and migration. Moreover, the combination of ACT001 and cisplatin showed a synergistic effect on the inhibition of glioma in vitro and in vivo. In conclusion, our findings demonstrate that PAI-1 is a new target of ACT001, the inhibition of PAI-1 induces glioma inhibition, and ACT001 has a synergistic effect with cisplatin through the inhibition of the PAI-1/PI3K/AKT pathway.
PAI-1 在癌症的发生、复发和多药耐药中发挥重要作用，在肿瘤中高度表达。ACT001 目前正在进行胶质母细胞瘤（GBM）治疗的 I 期临床试验。然而，ACT001 的详细分子机制尚不清楚。在这项研究中，我们研究了 ACT001 对神经胶质瘤细胞增殖的影响，并阐明了其机制。我们发现 PAI-1 是 ACT001 的直接靶标，通过细胞热转移试验证实。然后，通过 Biacore 测定、热稳定性测定和 ACT001 探针测定验证了 ACT001 与 PAI-1 之间的相互作用。此外，从蛋白质组学分析中，我们发现 ACT001 直接结合 PAI-1 以抑制 PI3K/AKT 通路，从而抑制神经胶质瘤细胞的增殖、侵袭和迁移。此外，ACT001 与顺铂联合使用对体外和体内抑制神经胶质瘤具有协同作用。总之，我们的研究结果表明 PAI-1 是 ACT001 的一个新靶点，抑制 PAI-1 诱导神经胶质瘤抑制，ACT001 通过抑制 PAI-1/PI3K/AKT 通路与顺铂具有协同作用。
