Knuefermann Christiane, Lu Yang, Liu Bolin, Jin Weidong, Liang Ke, Wu Ling, Schmidt Mathias, Mills Gordon B, Mendelsohn John, Fan Zhen
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
Oncogene. 2003 May 22;22(21):3205-12. doi: 10.1038/sj.onc.1206394.
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 Akt1 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.
生长因子受体介导的信号转导与癌细胞对传统化疗产生耐药性有关。在本研究中，我们描绘了一条涉及HER2/PI-3K/Akt介导人类乳腺癌细胞多药耐药性的途径。我们发现同时表达HER2和HER3的细胞系似乎具有更高水平的Akt磷酸化（活化的Akt）。在表达HER3的MCF7乳腺癌细胞中转染HER2会导致Akt的磷酸肌醇-3激酶（PI-3K）依赖性激活，并与细胞对多种化疗药物（紫杉醇、阿霉素、5-氟尿嘧啶、依托泊苷和喜树碱）的耐药性增加有关。用各自的显性负性表达载体选择性抑制PI-3K或Akt活性可使细胞对化疗药物诱导的凋亡敏感。我们进一步证明，表达组成型活性Akt的MCF7细胞（其中Akt的磷脂相互作用PH结构域被法尼基化序列取代以进行组成型膜锚定，即DeltaPH-Akt1-farn）对化疗药物也表现出类似的耐药性增加。我们的结果表明，HER2/PI-3K激活Akt1在赋予乳腺癌细胞广谱化疗耐药性方面起重要作用，因此Akt可能是改善乳腺癌患者治疗结果的新分子靶点。
