Blueberry phytochemicals inhibit growth and metastatic potential of MDA-MB-231 breast cancer cells through modulation of the phosphatidylinositol 3-kinase pathway.
Blueberry phytochemicals inhibit growth and metastatic potential of MDA-MB-231 breast cancer cells through modulation of the phosphatidylinositol 3-kinase pathway.
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DOI：
10.1158/0008-5472.can-09-3565
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发表时间：
2010-05-01
期刊：
影响因子：
11.2
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Adams LS;Phung S;Yee N;Seeram NP;Li L;Chen S
已知膳食植物化学物质具有多种抗癌特性。本研究在体外和体内研究了蓝莓提取物对三阴性乳腺癌细胞系的化学预防活性。蓝莓降低HCC 38、HCC 1937和MDA-MB-231细胞中的细胞增殖，而对非致瘤性MCF-10A细胞系没有影响。通过使用伤口愈合测定和通过PET膜的迁移抑制细胞运动性，显示蓝莓降低MDA-MB-231细胞的转移潜力。蓝莓处理降低了MDA-MB-231条件培养基中基质金属蛋白酶9的活性和尿激酶型纤溶酶原激活物的分泌，而增加了基质金属蛋白酶组织抑制剂-1和纤溶酶原激活物抑制剂-1的分泌。通过蛋白质印迹和报告基因测定研究了控制这些过程的表达/活化的细胞信号传导途径。蓝莓处理可降低MDA-MB-231细胞中磷脂酰肌醇3-激酶（PI 3 K）/AKT和核因子κ B（NFκB）的活性，而蛋白激酶C（PKC）和细胞外调节激酶（ERK）活性不受影响。在体内，使用MDA-MB-231异种移植模型评价蓝莓抑制三阴性乳腺肿瘤生长的功效。与对照组相比，蓝莓处理的小鼠的肿瘤重量和增殖（Ki-67表达）降低，其中凋亡（半胱天冬酶-3表达）增加。蓝莓喂养的小鼠肿瘤的免疫组织化学分析显示AKT和p65 NFκB信号蛋白的活化降低，而对ERK的磷酸化没有影响。这些数据说明蓝莓植物化学物质通过调节PI 3 K/AKT/NFκB途径对MDA-MB-231细胞的生长和转移潜力的抑制作用。
Dietary phytochemicals are known to exhibit a variety of anti-carcinogenic properties. This study investigated the chemopreventive activity of blueberry extract in triple negative breast cancer cell lines in vitro and in vivo. Blueberry decreased cell proliferation in HCC38, HCC1937 and MDA-MB-231 cells with no effect on the non-tumorigenic MCF-10A cell line. Decreased metastatic potential of MDA-MB-231 cells by blueberry was shown through inhibition of cell motility using wound healing assays and migration through a PET membrane. Blueberry treatment decreased the activity of matrix metalloproteinase 9 and the secretion of urokinase-type plasminogen activator while increasing tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1 secretion in MDA-MB-231 conditioned medium as shown by western blotting. Cell signaling pathways that control the expression/activation of these processes were investigated via western blotting and reporter gene assay. Treatment with blueberry decreased phosphatidylinositol 3-kinase (PI3K)/AKT and nuclear factor kappa-B (NFκB) activation in MDA-MB-231 cells where protein kinase C (PKC) and extracellular regulated kinase (ERK) were not affected. In vivo, the efficacy of blueberry to inhibit triple negative breast tumor growth was evaluated using the MDA-MB-231 xenograft model. Tumor weight and proliferation (Ki-67 expression) were decreased in blueberry treated mice, where apoptosis (caspase-3 expression) was increased compared to controls. Immunohistochemical analysis of tumors from blueberry-fed mice showed decreased activation of AKT and p65 NFκB signaling proteins with no effect on the phosphorylation of ERK. These data illustrate the inhibitory effect of blueberry phytochemicals on the growth and metastatic potential of MDA-MB-231 cells through modulation of the PI3K/AKT/NFκB pathway.