Microarray-assisted pathway analysis identifies mitogen-activated protein kinase signaling as a mediator of resistance to the green tea polyphenol epigallocatechin 3-gallate in Her-2/neu-overexpressing breast cancer cells
Microarray-assisted pathway analysis identifies mitogen-activated protein kinase signaling as a mediator of resistance to the green tea polyphenol epigallocatechin 3-gallate in Her-2/neu-overexpressing breast cancer cells
复制标题
DOI：
10.1158/0008-5472.can-05-4287
复制
发表时间：
2006-05-15
期刊：
影响因子：
11.2
通讯作者：
Sonenshein, Gail E.
中科院分区：
文献类型：
--
作者：
Guo, Shangqin;Lu, Jun;Sonenshein, Gail E.
乳腺癌中表皮生长因子受体家族成员Her-2/neu的过表达导致受体自身磷酸化并诱导多种下游信号传导途径，包括Akt激酶至核因子-κ B（NF-κ B）级联反应，其与不良预后相关。以前，我们发现绿色茶多酚表没食子儿茶素没食子酸酯（EGCG）通过减少受体自磷酸化和下游Akt和NF-κ B活性来抑制NF 639 Her-2/neu驱动的乳腺癌细胞的生长。有趣的是，在存在EGCG的情况下长时间培养后，可以分离出对多酚具有抗性的细胞。在这里，我们报告说，耐药细胞已经失去了酪氨酸磷酸化的Her-2/neu受体。令人惊讶的是，它们显示出升高的NF-κ B活性，并且抑制这种活性使细胞对EGCG敏感。对原始和耐药NF 639细胞群的微阵列研究数据进行基因集富集分析途径评估，其显示在耐药细胞中丝裂原活化蛋白激酶（MAPK）途径被激活。用MAPK抑制剂U 0216处理抗性细胞减少了软琼脂中的生长和侵袭表型，而EGCG和U 0216的组合导致具有鹅卵石上皮表型的细胞。因此，MAPK途径的激活介导了对EGCG的抗性。
Overexpression of the epidermal growth factor receptor family member Her-2/neu in breast cancer leads to autophosphorylation of the receptor and induction of multiple downstream signaling pathways, including the Akt kinase to nuclear factor-kappa B (NF-kappa B) cascade that is associated with poor prognosis. Previously, we showed that the green tea polyphenol epigallocatechin 3-gallate (EGCG) inhibits growth of NF639 Her-2/neu-driven breast cancer cells via reducing receptor autophosphorylation and downstream Akt and NF-kappa B activities. Interestingly, upon prolonged culture in the presence of EGCG, cells resistant to the polyphenol could be isolated. Here, we report that resistant cells have lost tyrosine phosphorylation on the Her-2/neu receptor. Surprisingly, they displayed elevated NF-kappa B activity, and inhibition of this activity sensitized cells to EGCG. Data from microarray studies of the original and resistant NF639 populations of cells were subjected to Gene Set Enrichment Analysis pathway assessment, which revealed that the mitogen activated protein kinase (MAPK) pathway was activated in the resistant cells. Treatment of the resistant cells with the MAPK inhibitor U0216 reduced growth in soft agar and invasive phenotype, whereas the combination of EGCG and U0216 resulted in cells with a cobblestone epithelial phenotype. Thus, activation of the MAPK pathway mediates resistance to EGCG.