Differential cellular and molecular effects of bortezomib, a proteasome inhibitor, in human breast cancer cells
Differential cellular and molecular effects of bortezomib, a proteasome inhibitor, in human breast cancer cells
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DOI：
10.1158/1535-7163.mct-05-0147
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发表时间：
2006-03-01
影响因子：
5.7
通讯作者：
Albanell, J
中科院分区：
文献类型：
--
作者：
Codony-Servat, J;Tapia, MA;Albanell, J
蛋白酶体抑制剂硼替佐米对乳腺癌细胞的细胞和分子效应的特征尚不清楚。在这里，在一组六个乳腺癌细胞系中，硼替佐米以浓度依赖性、时间依赖性和细胞系依赖性的方式降低生存力。蛋白酶体活性相对较高的三个更具抗性的细胞系中的两个。硼替佐米对细胞活力的影响与HER-2、表皮生长因子受体（EGFR）、AKT或细胞外信号调节激酶1/2（ERK 1/2）的表达/磷酸化之间没有关系。在SK-BR-3和BT-474细胞中进一步研究了硼替佐米的分子效应，因为它们共享EGFR表达和HER-2过表达，而相比之下，SK-BR-3细胞对该试剂的敏感性高200倍。蛋白酶体活性在两种细胞系中被抑制到相似的程度，并且已知的蛋白酶体底物积累相似。在SK-BR-3细胞中，在临床相关浓度的硼替佐米下观察到EGFR、HER-2和AKT磷酸化的显著抑制。与此相反，磷酸化Raf/促分裂原活化蛋白激酶1/2（MEK 1/2）/ERK 1/2增加硼替佐米。在BT-474细胞中，效果要不那么明显。用硼替佐米与EGFR、磷脂酰肌醇X-激酶或MEK的药理学抑制剂组合治疗SK-BR-3细胞导致对细胞活力的作用适度增强或不增强。总的来说，这些结果表明硼替佐米在人乳腺癌细胞中具有不同的细胞和分子效应。观察到的硼替佐米对信号转导分子的影响可能有助于设计基于机制的联合治疗。
The cellular and molecular effects of the proteasome inhibitor bortezomib on breast cancer cells are as yet poorly characterized. Here, in a panel of six breast cancer cell lines, bortezomib reduced viability in a concentration-dependent, time-dependent, and cell line-dependent manner. Proteasome activity was relatively high in two of the three more resistant cell lines. No relationship was observed between bortezomib effects on cell viability and expression/phosphorylation of HER-2, epidermal growth factor receptor (EGFR), AKT, or extracellular signal-regulated kinase 1/2 (ERK1/2). Molecular effects of bortezomib were further studied in SK-BR-3 and BT-474 cells because they share expression of EGFR and overexpression of HER-2 while, in contrast, SK-BR-3 cells were 200-fold more sensitive to this agent. Proteasome activity was inhibited to a similar extent in the two cell lines, and known proteasome substrates accumulated similarly. In SK-BR-3 cells, a marked inhibition of EGFR, HER-2, and AKT phosphorylation was observed at a clinically relevant concentration of bortezomib. In contrast, phosphorylation of Raf/mitogen-activated protein kinase kinase 1/2 (MEK 1/2)/ERK1/2 increased by bortezomib. In BT-474 cells, the effects were much less pronounced. Treatment of SK-BR-3 cells with bortezomib combined with pharmacologic inhibitors of EGFR, phosphatidylinositol X-kinase, or MEK resulted in modest or no enhancement of the effects on cell viability. Collectively, these results show that bortezomib has differential cellular and molecular effects in human breast cancer cells. The bortezomib-observed effects on signaling transduction molecules might be relevant to help to design mechanistic-based combination treatments.