Upregulation of PKC-δ contributes to antiestrogen resistance in mammary tumor cells
Upregulation of PKC-δ contributes to antiestrogen resistance in mammary tumor cells
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DOI：
10.1038/sj.onc.1208502
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发表时间：
2005-04-28
期刊：
影响因子：
8
通讯作者：
Reddy, KB
中科院分区：
文献类型：
--
作者：
Nabha, SM;Glaros, S;Reddy, KB
乳腺癌患者对他莫昔芬（Tam）的获得性耐药是一个严重的治疗问题。我们以前曾报道，蛋白激酶C-δ（PKC-δ）在雌激素（E2）介导的细胞增殖中起着重要作用。为了确定PKC-δ是否是在Tam存在下支持细胞生长的主要替代信号通路之一，我们确定了四种不同抗雌激素抗性细胞模型中PKC亚型的水平。与敏感细胞相比，四种抗雌激素抗性细胞系中的三种（Tam/MCF-7、ICI/MCF-7和HER-2/MCF-7）表达显著高水平的总PKC-δ水平和活化PKC-δ水平。雌激素受体（ER）α的含量和功能在所有抗雌激素耐药细胞系中保持不变。在Tam敏感的MCF-7细胞中过表达活性PKC-δ（PKC-δ/ MCF-7）导致体外和体内Tam抗性。通过rottlerin（PKC-δ的相对特异性抑制剂）或siRNA抑制PKC-δ显著抑制抗雌激素抗性细胞中雌激素和TAM诱导的生长。在异种移植模型中，与TAM敏感性肿瘤相比，TAM耐药肿瘤中的PKC-δ水平显著更高（P
Acquired resistance to tamoxifen (Tam) in breast cancer patients is a serious therapeutic problem. We have previously reported that protein kinase C-delta (PKC-delta) plays a major role in estrogen (E2)-mediated cell proliferation. To determine if PKC-delta is one of the major alternate signaling pathways that supports cell growth in the presence of Tam, we determined the levels of PKC isoforms in four different models of antiestrogen-resistant cells. Three out of four antiestrogen resistance cell lines (Tam/MCF-7, ICI/MCF-7 and HER-2/MCF-7) expressed significantly high levels of both total and activated PKC-delta levels compared to sensitive cells. Estrogen receptor ( ER) alpha content and function are maintained in all the antiestrogen-resistant cell lines. Overexpressing active PKC-delta in Tam-sensitive MCF-7 cells (PKC-delta/ MCF-7) led to Tam resistance both in vitro and in vivo. Inhibition of PKC-delta by rottlerin ( a relatively specific inhibitor of PKC-delta) or siRNA significantly inhibited estrogen- and Tam-induced growth in antiestrogen-resistant cells. PKC-delta levels are significantly higher in Tam-resistant tumors compared to Tam-sensitive tumors in xenograft model (P