ABSTRACT

Glioblastoma multiforme (GBM) is the most aggressive primary brain cancer and this is due to cancer cells being apoptosis-resistant and having increased cell proliferation, migration, invasion, and angiogenesis properties. Previous studies have indicated both STAT and Notch pathways being important for initiation and progression in GBM. In this work, we first studied the effects of STAT inhibitors on Notch signalling using small molecule STAT inhibitors. It was observed that STAT inhibitors surprisingly activated Notch signalling by inducing NICD and Notch target genes in GBM cells. Thus, we aimed to combine STAT inhibitor treatment with a Notch pathway inhibitor and study effects on GBM tumourigenesis. STAT5 inhibitor (Pimozide) and STAT3 inhibitor (S3I-201) were individually used in combination with γ-secretase inhibitor (DAPT), an inhibitor of Notch signalling, in a panel of GBM cells for cell proliferation and epithelial plasticity changes. Compared with single-agent treatments, combinatorial treatments with the STAT and Notch inhibitors significantly increased apoptosis in the treated cells, impairing cell proliferation, migration, and invasion. These findings suggest that concurrent blocking of STAT and Notch signalling pathways could provide added therapeutic benefit for the treatment of glioblastoma.

摘要

多形性胶质母细胞瘤 (GBM) 是最具侵袭性的原发性脑癌，这是由于癌细胞具有抗凋亡能力并且具有增加的细胞增殖、迁移、侵袭和血管生成特性。先前的研究表明 STAT 和 Notch 通路对 GBM 的起始和进展都很重要。在这项工作中，我们首先使用小分子 STAT 抑制剂研究了 STAT 抑制剂对 Notch 信号传导的影响。据观察，STAT 抑制剂通过在 GBM 细胞中诱导 NICD 和 Notch 靶基因，令人惊讶地激活了 Notch 信号。因此，我们旨在将 STAT 抑制剂治疗与 Notch 通路抑制剂相结合，并研究对 GBM 肿瘤发生的影响。STAT5抑制剂（Pimozide）和STAT3抑制剂（S3I-201）分别与γ-分泌酶抑制剂（DAPT）联合使用，在一组 GBM 细胞中用于细胞增殖和上皮可塑性变化的 Notch 信号抑制剂。与单药治疗相比，STAT 和 Notch 抑制剂联合治疗显着增加了治疗细胞的凋亡，削弱了细胞增殖、迁移和侵袭。这些发现表明，同时阻断 STAT 和 Notch 信号通路可以为胶质母细胞瘤的治疗提供额外的治疗益处。