Identification of signal transduction pathways involved in constitutive NF-κB activation in breast cancer cells
Identification of signal transduction pathways involved in constitutive NF-κB activation in breast cancer cells
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DOI：
10.1038/sj.onc.1205243
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发表时间：
2002-03-21
期刊：
影响因子：
8
通讯作者：
Nakshatri, H
中科院分区：
文献类型：
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作者：
Bhat-Nakshatri, P;Sweeney, CJ;Nakshatri, H
核因子-κ B（NF-κ B）通常通过其与κ B抑制剂（IkappaB）蛋白的结合而在细胞质中以非活性形式维持，并且在用多种信号刺激细胞时被激活。然而，在包括乳腺癌在内的许多癌症中观察到NF-κ B的组成性激活。参与组成性NF-κ B激活的信号通路在很大程度上仍然未知。使用来自转基因小鼠的乳腺癌细胞系，过表达特定的癌基因/生长因子在乳腺，我们表明，heregulin，而不是her 2/neu，c-Myc或v-Ha-ras起着重要的作用，在组成性NT-kappaB激活。Her 2/neu增强肿瘤坏死因子α（TNF α）诱导的NF-κ B活化，而c-Myc增强12-o-四癸基佛波醇-13-乙酸酯（TPA）诱导的NT-κ B活化。调蛋白介导的NF-κ B活化与表皮生长因子受体（EGFR）和ErbB 3的磷酸化相关，但与her 2/neu无关。Tryphostin AG 1517抑制heregulin介导的EGFR、her 2/neu和ErbB 3的磷酸化，减少NF-κ B活化。相反，大黄素，它阻止her 2/neu的磷酸化heregulin，未能减少NF-κ B激活。这些结果表明，heregulin诱导NF-κ B独立于her 2/neu。PI 3激酶/AKT、蛋白激酶A（PKA）和IkappaB激酶似乎是参与NF-κ B活化的下游信号分子，因为这些激酶的特异性抑制剂而非ERK/MAP激酶或蛋白激酶C的抑制剂降低调蛋白介导的NF-κ B活化。基于这些结果，我们提出heregulin通过自分泌激活NF-κ B增加癌细胞中促侵袭、促转移和抗凋亡基因的表达，从而导致乳腺癌的侵袭性和耐药性生长。
Nuclear factor-kappaB (NF-kappaB) is usually maintained in an, inactive form in the cytoplasm through its association with inhibitor of kappaB (IkappaB) proteins, and is activated upon stimulation of cells with a variety of signals. However, constitutive activation of NF-kappaB is observed in a number of cancers including breast cancer. The signaling pathways that are involved in constitutive NF-kappaB activation remain largely unknown. Using breast cancer cell lines derived from transgenic mice that overexpress specific oncogene/growth factors in the mammary gland, we show that heregulin but not her2/neu, c-Myc or v-Ha-ras plays a major role in constitutive NT-kappaB activation. Her2/neu potentiated tumor necrosis factor alpha (TNFchi)-inducible NF-kappaB activation whereas c-Myc potentiated 12-o-tetracecanyolphorbol-13-acetate (TPA)-induced NT-kappaB activation. Heregulin-mediated NF-kappaB activation correlated with phosphorylation of epidermal growth factor receptor (EGFR) and ErbB3 but not her2/neu. Tryphostin AG1517, which inhibits heregulin-mediated phosphorylation of EGFR, her2/neu and ErbB3 reduced NF-kappaB activation. In contrast, emodin, which blocks phosphorylation of her2/neu by heregulin, failed to reduce NF-kappaB activation. These results suggest that heregulin induces NF-kappaB independent of her2/neu. PI3 kinase/AKT, protein kinase A (PKA) and IkappaB kinase appear to be downstream signaling molecules involved in NF-kappaB activation as specific inhibitors of these kinases but not inhibitors of ERK/MAP kinase or protein kinase C reduced heregulin-mediated NF-kappaB activation. Based on these results, we propose that heregulin increases the expression of pro-invasive, prometastatic and anti-apoptotic genes in cancer cells through autocrine activation of NF-kappaB, which leads to invasive and drug-resistant growth of breast cancer.