NF-κB regulates radioresistance mediated by β1-integrin in three-dimensional culture of breast cancer cells.
NF-κB regulates radioresistance mediated by β1-integrin in three-dimensional culture of breast cancer cells.
复制标题
DOI：
10.1158/0008-5472.can-12-3537
复制
发表时间：
2013-06-15
期刊：
影响因子：
11.2
通讯作者：
Park CC
中科院分区：
文献类型：
--
作者：
Ahmed KM;Zhang H;Park CC
β1-整合素诱导增强乳腺癌细胞暴露于电离辐射（IR）后的存活，但这种作用的机制仍不清楚。尽管NF-κB在IR后启动促存活信号传导途径，但NF-κB与辐射抗性中的其他关键元件的分子功能，特别是关于细胞外基质诱导的信号传导，尚不清楚。我们在β1整合素启动子区发现了一个典型的NF-κB结合位点，提示NF-κB可能具有调节作用。利用三维层粘连蛋白丰富的细胞外基质（3D lrECM）培养，我们发现NF-κB是T4-2乳腺癌细胞IR后β1-整合素反式激活所必需的。抑制NF-κB可降低克隆形成存活率，并诱导形成的肿瘤集落的凋亡和细胞停滞。此外，抑制NF-κB活性的T4-2肿瘤在无胸腺小鼠中表现出生长下降，IR通过下调β1-整合素表达进一步降低。β1-整合素和NF-κB p65之间的直接相互作用在非恶性乳腺上皮细胞中被诱导，但在恶性细胞中不被诱导，表明环境特异性调节。由于β1-整合素也激活NF-κB，我们的研究结果揭示了一种新的前向反馈途径，可以靶向增强治疗。
β1-integrin induction enhances breast cancer cell survival after exposure to ionizing radiation (IR), but the mechanisms of this effect remain unclear. Although NF-κB initiates prosurvival signaling pathways post-IR, the molecular function of NF-κB with other key elements in radioresistance, particularly with respect to extracellular matrix-induced signaling, is not known. We discovered a typical NF-κB binding site in the β1-integrin promoter region, indicating a possible regulatory role for NF-κB. Using 3-dimensional laminin-rich extracellular matrix (3D lrECM) culture, we show that NF-κB is required for β1-integrin transactivation in T4-2 breast cancer cells post-IR. Inhibition of NF-κB reduced clonogenic survival, and induced apoptosis and cytostasis in formed tumor colonies. In addition, T4-2 tumors with inhibition of NF-κB activity exhibit decreased growth in athymic mice, which was further reduced by IR with downregulated β1-integrin expression. Direct interactions between β1-integrin and NF-κB p65 were induced in non-malignant breast epithelial cells, but not in malignant cells, indicating context specific regulation. Since β1-integrin also activates NF-κB, our findings reveal a novel forward feedback pathway that could be targeted to enhance therapy.