Neuropilin-1 is expressed by breast cancer stem-like cells and is linked to NF-κB activation and tumor sphere formation
Neuropilin-1 is expressed by breast cancer stem-like cells and is linked to NF-κB activation and tumor sphere formation
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DOI：
10.1016/j.bbrc.2012.07.151
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发表时间：
2012-09-07
影响因子：
3.1
通讯作者：
Prud'homme, Gerald J.
中科院分区：
文献类型：
--
作者：
Glinka, Yelena;Mohammed, Nada;Prud'homme, Gerald J.
癌症干细胞（CSC）引发肿瘤并且对常规癌症疗法具有高抗性。曲尼司特是一种低毒性的口服活性药物，对乳腺CSC发挥抑制作用。这似乎取决于其芳烃受体（AHR）激动活性，但这种受体具有不同的功能，目前还不清楚CSC是如何被抑制的。CSC在低粘附培养物中产生肿瘤球，我们采用乳腺球形成测定作为乳腺CSC的功能测试。由于NF-κ B在乳腺球形成和CSC介导的肿瘤发生中起关键作用，我们研究了该途径。我们还研究了神经纤毛蛋白-1（Nrp 1）的作用，Nrp 1是一种与某些CSC的致瘤性相关的生长因子辅助受体。我们发现曲尼司特同时抑制乳腺球形成、Nrp 1表达和组成性NF-κ B激活。流式细胞术分析显示，乳腺癌细胞的一个亚群轴承乳腺CSC标志物也表达Nrp 1。阻断性抗Nrp 1抗体抑制乳腺球形成。我们研究了Nrp 1和NF-κ B激活之间是否存在联系。siRNA敲低Nrp 1严重抑制NF-κ B活化和乳腺球形成。Akt和ERK 1/2的磷酸化也减少，但程度较轻。我们的结论是Nrp 1在乳腺球形成中起着关键作用，这种活性与NF-κ B激活有关。因此，Nrp 1可能是治疗乳腺癌干细胞的靶点，抗癌药物曲尼司特抑制其表达。(C)2012 Elsevier Inc. All rights reserved.
Cancer stem cells (CSCs) initiate tumors and have a high resistance to conventional cancer therapy. Tranilast is an orally active drug of low toxicity that exerts inhibitory effects on breast CSCs. This appears to depend on its aryl hydrocarbon receptor (AHR) agonistic activity, but this receptor has diverse functions and it is unclear how CSCs are inhibited. CSCs generate tumor spheres in low-adherence cultures, and we employed the mammosphere-forming assay as a functional test for breast CSCs. Because NF-kappa B has a key role in mammosphere formation and CSC-mediated tumor initiation, we examined that pathway. We also examined the role of neuropilin-1 (Nrp1), which is a growth factor coreceptor linked to the tumorigenicity of some CSCs. We found that tranilast concurrently suppressed mammosphere formation, Nrp1 expression and constitutive NF-kappa B activation. Flow cytometric analysis revealed that a subpopulation of breast cancer cells bearing breast CSC markers also expressed Nrp1. A blocking anti-Nrp1 antibody suppressed mammosphere formation. We examined whether there was a link between Nrp1 and NF-kappa B activation. The siRNA knockdown of Nrp1 severely suppressed NF-kappa B activation and mammosphere formation. The phosphorylation of Akt and ERK1/2 was also reduced, but to a lesser extent. We conclude that Nrp1 plays a key role in mammosphere formation and this activity is linked to NF-kappa B activation. Thus, Nrp1 might be a target for therapy against breast CSCs, and the anticancer drug tranilast suppresses its expression. (C) 2012 Elsevier Inc. All rights reserved.