Xiao Hui, Bid Hemant Kumar, Jou David, Wu Xiaojuan, Yu Wenying, Li Chenglong, Houghton Peter J, Lin Jiayuh
From the Department of Pediatrics, College of Medicine, Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio 43205 and.
the Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210.
J Biol Chem. 2015 Feb 6;290(6):3418-29. doi: 10.1074/jbc.M114.616748. Epub 2014 Oct 13.
Signal transducers and activators of transcription 3 (STAT3) signaling is persistently activated and could contribute to tumorigenesis of medulloblastoma. Numerous studies have demonstrated that inhibition of the persistent STAT3 signaling pathway results in decreased proliferation and increased apoptosis in human cancer cells, indicating that STAT3 is a viable molecular target for cancer therapy. In this study, we investigated a novel non-peptide, cell-permeable small molecule, named LY5, to target STAT3 in medulloblastoma cells. LY5 inhibited persistent STAT3 phosphorylation and induced apoptosis in human medulloblastoma cell lines expressing constitutive STAT3 phosphorylation. The inhibition of STAT3 signaling by LY5 was confirmed by down-regulating the expression of the downstream targets of STAT3, including cyclin D1, bcl-XL, survivin, and micro-RNA-21. LY5 also inhibited the induction of STAT3 phosphorylation by interleukin-6 (IL-6), insulin-like growth factor (IGF)-1, IGF-2, and leukemia inhibitory factor in medulloblastoma cells, but did not inhibit STAT1 and STAT5 phosphorylation stimulated by interferon-γ (IFN-γ) and EGF, respectively. In addition, LY5 blocked the STAT3 nuclear localization induced by IL-6, but did not block STAT1 and STAT5 nuclear translocation mediated by IFN-γ and EGF, respectively. A combination of LY5 with cisplatin or x-ray radiation also showed more potent effects than single treatment alone in the inhibition of cell viability in human medulloblastoma cells. Furthermore, LY5 demonstrated a potent inhibitory activity on cell migration and angiogenesis. Taken together, these findings indicate LY5 inhibits persistent and inducible STAT3 phosphorylation and suggest that LY5 is a promising therapeutic drug candidate for medulloblastoma by inhibiting persistent STAT3 signaling.
信号转导与转录激活因子3（STAT3）信号通路持续激活，可能促进髓母细胞瘤的发生。大量研究表明，抑制持续的STAT3信号通路可导致人类癌细胞增殖减少、凋亡增加，这表明STAT3是癌症治疗中一个可行的分子靶点。在本研究中，我们研究了一种新型的非肽、可穿透细胞的小分子，名为LY5，用于靶向髓母细胞瘤细胞中的STAT3。LY5抑制持续的STAT3磷酸化，并在表达组成型STAT3磷酸化的人类髓母细胞瘤细胞系中诱导凋亡。LY5对STAT3信号通路的抑制作用通过下调STAT3下游靶点的表达得以证实，这些靶点包括细胞周期蛋白D1、bcl-XL、生存素和微小RNA-21。LY5还抑制了髓母细胞瘤细胞中白细胞介素-6（IL-6）、胰岛素样生长因子（IGF）-1、IGF-2和白血病抑制因子诱导的STAT3磷酸化，但不抑制分别由干扰素-γ（IFN-γ）和表皮生长因子（EGF）刺激的STAT1和STAT5磷酸化。此外，LY5阻断了IL-6诱导的STAT3核定位，但不分别阻断IFN-γ和EGF介导的STAT1和STAT5核转位。LY5与顺铂或X射线辐射联合使用在抑制人类髓母细胞瘤细胞活力方面也比单独使用单一治疗显示出更强的效果。此外，LY5对细胞迁移和血管生成表现出强大的抑制活性。综上所述，这些发现表明LY5抑制持续和可诱导的STAT3磷酸化，并提示LY5通过抑制持续的STAT3信号通路是一种有前景的髓母细胞瘤治疗药物候选物。
