Up-regulation of breast cancer resistance protein plays a role in HER2-mediated chemoresistance through PI3K/Akt and nuclear factor-kappa B signaling pathways in MCF7 breast cancer cells
Up-regulation of breast cancer resistance protein plays a role in HER2-mediated chemoresistance through PI3K/Akt and nuclear factor-kappa B signaling pathways in MCF7 breast cancer cells
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DOI：
10.1093/abbs/gmr050
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发表时间：
2011-08-01
影响因子：
3.7
通讯作者：
He, Zhimin
中科院分区：
文献类型：
--
作者：
Zhang, Weijia;Ding, Wei;He, Zhimin
人表皮生长因子受体2（HER 2/neu，也称为ErbB 2）过表达与癌症的不良预后和化疗耐药性相关。乳腺癌耐药蛋白（BCRP和ABCG 2）是一种药物外排泵，负责多种癌细胞的多药耐药（MDR）。HER 2和BCRP与乳腺癌患者的不良治疗反应相关，尽管HER 2和BCRP表达之间的关系尚不清楚。在此，我们发现HER 2转染入MCF 7乳腺癌细胞（MCF 7/HER 2）通过磷脂酰肌醇3-激酶（PI 3 K）/Akt和核因子-κ B（NF-κ B）信号转导导致BCRP上调。用PI 3 K抑制剂LY 294002、IkB磷酸化抑制剂Bay 11 -7082和IkB α显性失活突变体处理MCF/HER 2细胞可抑制HER 2诱导的BCRP启动子活性。此外，我们发现HER 2过表达导致MCF 7细胞对多种抗肿瘤药物如紫杉醇（Taxol）、顺铂（DDP）、依托泊苷（VP-16）、阿霉素（ADM）、米托蒽醌（MX）和5-氟尿嘧啶（5-FU）的耐药性增加。此外，沉默BCRP的表达或选择性抑制Akt或NF-κ B的活性至少部分地使MCF 7/HER 2细胞对这些化疗剂敏感。综上所述，通过PI 3 K/AKT/NF-κ B信号通路上调BCRP在HER 2介导的MCF 7细胞化疗耐药中起重要作用，AKT、NF-κ B和BCRP通路可能成为治疗干预的潜在靶点。
Human epidermal growth factor receptor 2 (HER2/neu, also known as ErbB2) overexpression is correlated with the poor prognosis and chemoresistance in cancer. Breast cancer resistance protein (BCRP and ABCG2) is a drug efflux pump responsible for multidrug resistance (MDR) in a variety of cancer cells. HER2 and BCRP are associated with poor treatment response in breast cancer patients, although the relationship between HER2 and BCRP expression is not clear. Here, we showed that transfection of HER2 into MCF7 breast cancer cells (MCF7/HER2) resulted in an up-regulation of BCRP via the phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B (NF-kappa B) signaling. Treatment of MCF/HER2 cells with the PI3K inhibitor LY294002, the IkB phosphorylation inhibitor Bay11-7082, and the dominant negative mutant of IkB alpha inhibited HER2-induced BCRP promoter activity. Furthermore, we found that HER2 overexpression led to an increased resistance of MCF7 cells to multiple antitumor drugs such as paclitaxel (Taxol), cisplatin (DDP), etoposide (VP-16), adriamycin (ADM), mitoxantrone (MX), and 5-fluorouracil (5-FU). Moreover, silencing the expression of BCRP or selectively inhibiting the activity of Akt or NF-kappa B sensitized the MCF7/HER2 cells to these chemotherapy agents at least in part. Taken together, up-regulation of BCRP through PI3K/AKT/NF-kappa B signaling pathway played an important role in HER2-mediated chemoresistance of MCF7 cells, and AKT, NF-kappa B, and BCRP pathways might serve as potential targets for therapeutic intervention.