HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells
HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells
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DOI：
10.1038/sj.onc.1206394
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发表时间：
2003-05-22
期刊：
影响因子：
8
通讯作者：
Fan, Z
中科院分区：
文献类型：
--
作者：
Knuefermann, C;Lu, Y;Fan, Z
生长因子受体介导的信号转导已涉及赋予癌细胞对常规化疗的抗性。在这项研究中，我们描绘了一个途径，涉及HER 2/PI-3 K/Akt介导的多药耐药的人乳腺癌细胞。我们发现，同时表达HER 2和HER 3的细胞系似乎具有更高的Akt磷酸化水平（活化的Akt）。在表达HER 2的MCF 7乳腺癌细胞中转染HER 2。HER 3引起Akt的磷酸肌醇-3激酶（PI-3 K）依赖性活化，并且与细胞对多种化疗剂（紫杉醇、多柔比星、5-氟尿嘧啶、依托泊苷和喜树碱）的抗性增加相关。选择性抑制PI-3 K或Akt活性与各自的显性负性表达载体敏化细胞诱导的化疗药物的细胞凋亡。我们进一步证明，MCF 7细胞表达的组成型活性Akt，其中Akt的磷脂相互作用的PH结构域被取代的法尼基化序列，组成型膜锚定（DeltaPH-Akt 1-farn），表现出类似的耐药性增加化疗药物。我们的研究结果表明，通过HER 2/PI-3 K激活AM在赋予乳腺癌细胞广谱化疗耐药性方面起着重要作用，因此Akt可能是一种新的分子靶点，用于改善乳腺癌患者的预后。
Growth factor receptor-mediated signal transduction has been implicated in conferring resistance to conventional chemotherapy on cancer cells. In this study, we delineated a pathway that involves HER2/PI-3K/Akt in mediating multidrug resistance in human breast cancer cells. We found that the cell lines that express both HER2 and HER3 appear to have a higher phosphorylation level of Akt (activated Akt). Transfection of HER2 in MCF7 breast cancer cells that express. HER3 caused a phosphoinoside-3 kinase (PI-3K)-dependent activation of Akt, and was associated with an increased resistance of the cells to multiple chemotherapeutic agents (paclitaxel, doxorubicin, 5-fluorouracil, etoposide, and camptothecin). Selective inhibition of PI-3K or Akt activity with their respective dominant-negative expression vectors sensitized the cells to the induction of apoptosis by the chemotherapeutic agents. We further demonstrated that MCF7 cells expressing a constitutively active Akt, in which the phospholipid-interactive PH domain of Akt was replaced by a farnesylation sequence for, constitutive membrane anchorage (DeltaPH-Akt1-farn), showed a similar increased resistance to the chemotherapeutic agents. Our results suggest that activation of AM by HER2/PI-3K plays an important role in conferring a broad-spectrum chemoresistance on breast cancer cells and that Akt may therefore be a novel molecular target for therapies that would improve the outcome of patients with breast cancer.