Abstract：
Aberration of Notch signaling is one of the key events involved in the development and progression of head and neck squamous cell carcinoma (HNSCC). The Notch pathway controls the tissue-specific differentiation of normal squamous epithelial cells and is frequently altered in squamous carcinomas, thus affecting their proliferation, growth, survival, and chemosensitivity or resistance against anti-cancer agents. In this study, we show that the use of novel, small-molecule inhibitors of Notch signaling, such as FLI-06, can have a beneficial effect on increasing the chemosensitivity of HNSCC to taxane-based chemotherapy. Inhibition of Notch signaling by FLI-06 alone virtually blocks the proliferation and growth of HNSCC cells in both 2D and 3D cultures and the zebrafish model, which is accompanied by down-regulation of key Notch target genes and proteins. Mechanistically, FLI-06 treatment causes cell cycle arrest in the G1-phase and induction of apoptosis in HNSCC, which is accompanied by increased c-JunS63 phosphorylation. Combining FLI-06 with Docetaxel shows a synergistic effect and partially blocks the cell growth of aggressive HNSCC cells via enhanced apoptosis and modification of c-JunS243 phosphorylation via GSK-3β inhibition. In conclusion, inhibition of Notch signaling in HNSCC cells that retain active Notch signaling significantly supports taxane-based anticancer activities via modulation of both the GSK-3β and the c-Jun.
摘要：
Notch信号传导异常是头颈部鳞状细胞癌(HNSCC)发生发展的关键事件之一。Notch通路控制正常鳞状上皮细胞的组织特异性分化，并且在鳞癌中经常发生改变。从而影响它们的扩散，增长,生存,以及对抗癌药物的化学敏感性或耐药性。在这项研究中,我们展示了小说的使用，Notch信号的小分子抑制剂，例如FLI-06可以对增加HNSCC对基于紫杉烷的化疗的化学敏感性具有有益作用。通过FLI-06单独抑制Notch信号传导实际上阻断了HNSCC细胞在2D和3D培养和斑马鱼模型中的增殖和生长。这伴随着关键的Notch靶基因和蛋白质的下调。机械上,FLI-06处理导致细胞周期停滞在G1期，并诱导HNSCC细胞凋亡，伴随着c-JunS63磷酸化的增加。FLI-06与多西他赛的组合显示出协同作用，并通过GSK-3β抑制增强的细胞凋亡和c-JunS243磷酸化的修饰部分阻断侵袭性HNSCC细胞的细胞生长。总之,通过调节GSK-3β和c-Jun，抑制保留活性Notch信号的HNSCC细胞中的Notch信号显着支持基于紫杉烷的抗癌活性。
