Inhibition of the Wnt-β-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy.
Inhibition of the Wnt-β-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy.
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DOI：
10.1016/j.bbrc.2012.12.118
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发表时间：
2013-02-08
影响因子：
3.1
通讯作者：
Li, Tian-Fang
中科院分区：
文献类型：
--
作者：
Ma, Yimin;Ren, Yongxin;Han, Ethan Q.;Li, Huiwu;Chen, Di;Jacobs, Joshua J.;Gitelis, Steven;O'Keefe, Regis J.;Konttinen, Yrjo T.;Yin, Guoyong;Li, Tian-Fang
骨肉瘤是青少年早期最常见的恶性骨肿瘤之一。多药化疗使5年生存率从20%提高到70%。然而，30年来，这一比率一直令人震惊，复发和转移患者的预后特别差。我们的研究旨在探讨Wnt-β-catenin、Notch和Hedgehog通路在OS发生中的作用，因为所有这些通路都参与了骨骼发育、肿瘤发生和化疗耐药性。我们的研究结果表明，Wnt-β-catenin信号通路中的主要成分，如Wnt 3a、β-catenin和Lef 1，在人骨肉瘤细胞系Saos 2中的表达水平与人胎儿成骨细胞（hFOB）相比持续上调，而Notch和Hh信号分子的表达水平变化不一致。敲低β-catenin增加Saos 2对甲氨蝶呤（MTX）诱导的细胞死亡的敏感性。结论：β-catenin蛋白表达水平与OS的侵袭性相关，在高级别OS中表达更强。化学抑制Wnt-β-catenin信号增强MTX介导的Saos 2细胞死亡。当同时使用Wnt-β-catenin和Notch途径的两种抑制剂时，观察到与MTX的协同效应，而添加Hh抑制剂没有进一步提高功效。我们的研究结果为OS的发病机制提供了一些新的见解，并为将来应用Wnt-β-catenin和Notch抑制剂与目前使用的化疗药物一起改善OS的治疗结果奠定了基础。
Osteosarcoma (OS) is one of the most common malignant bone tumors in early adolescence. Multi-drug chemotherapy has greatly increased the five year survival rate from 20% to 70%. However, the rate has been staggering for 30 years and the prognosis is particularly poor for patients with recurrence and metastasis. Our study aimed to investigate the role of Wnt-β-catenin, Notch and Hedgehog pathway in OS development because all these pathways are involved in skeletal development, tumorigenesis and chemoresistance. Our results showed that the major components in Wnt-β-catenin pathway, e.g. Wnt3a, β-catenin and Lef1, were consistently upregulated in human osteosarcoma cell line Saos2 cells compared to human fetal osteoblasts (hFOB), whereas the changes in the expression levels of Notch and Hh signaling molecules were not consistent. Knocking down β-catenin increased the Saos2 sensitivity to methotrexate (MTX) induced cell death. Consistently, the expression level of β-catenin protein correlated with the invasiveness of OS, as evidenced by more intensive β-catenin immunoreactivity in higher grade OS samples. Chemical inhibition of the Wnt-β-catenin signaling enhanced MTX mediated death of Saos2 cells. A synergistic effect with MTX was observed when both inhibitors for Wnt-β-catenin and Notch pathways were simultaneously used, while the addition of the Hh inhibitor did not further improve the efficacy. Our findings provide some novel insight to OS pathogenesis and lay a foundation for future application of Wnt-β-catenin and Notch inhibitors together with the currently used chemotherapeutic drugs to improve the outcome of OS treatment.
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DOI：
10.1111/j.1749-6632.2009.05307.x
发表时间：
2010-01-01
期刊：
SKELETAL BIOLOGY AND MEDICINE
影响因子：
--
作者：
Tao, Jianning;Chen, Shan;Lee, Brendan
通讯作者：
Lee, Brendan
影响因子：
4
作者：
Iwaya, K;Ogawa, H;Mukai, K
通讯作者：
Mukai, K
影响因子：
15.9
作者：
Kansara, Maya;Tsang, Michael;Thomas, David M.
通讯作者：
Thomas, David M.
影响因子：
1.8
作者：
Warzecha, J.;Goettig, S.;Kurth, A.
通讯作者：
Kurth, A.
DOI：
10.2165/00148581-200810050-00005
发表时间：
2008-01-01
期刊：
Paediatric drugs
影响因子：
--
作者：
Chou, Alexander J;Geller, David S;Gorlick, Richard
通讯作者：
Gorlick, Richard