Palmitate-induced ER stress increases trastuzumab sensitivity in HER2/neu-positive breast cancer cells.
Palmitate-induced ER stress increases trastuzumab sensitivity in HER2/neu-positive breast cancer cells.
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DOI：
10.1186/s12885-016-2611-8
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发表时间：
2016-07-27
期刊：
影响因子：
3.8
通讯作者：
Conklin DS
中科院分区：
文献类型：
--
作者：
Baumann J;Wong J;Sun Y;Conklin DS
HER 2/neu阳性乳腺癌细胞最近被证明使用独特的Warburg样代谢来生存和攻击行为。与正常乳腺细胞或其他肿瘤细胞相比，这些细胞表现出增加的脂肪酸合成和储存。这种合成过程的破坏导致细胞凋亡。由于添加生理剂量的外源性棕榈酸酯诱导HER 2/neu阳性乳腺癌细胞中的细胞死亡，因此该途径可能在这些细胞中以其极限运行。我们研究了HER 2/neu阳性乳腺癌细胞对生理浓度的外源性棕榈酸酯的反应，以确定这种生理学的脂毒性相关后果。由于流行病学数据显示，富含饱和脂肪酸的饮食与HER 2/neu阳性癌症的发展呈负相关，因此这种细胞生理学可能与疾病的病因学和治疗相关。我们试图确定在HER 2/neu阳性乳腺癌细胞中由外源性棕榈酸生理浓度调节的信号通路，并深入了解分子机制及其与疾病预防和治疗的相关性。进行转录谱分析以评估在HER 2正常MCF 7和HER 2/neu阳性SKBR 3乳腺癌细胞中响应于外源棕榈酸酯而调节的程序。计算分析用于定义和预测功能关系，并确定在两种细胞系中差异调节的网络。这些预测进行了测试，使用报告分析，基于荧光的高含量显微镜，流式细胞术和免疫印迹。在HER 2/neu阳性BT474和HCC 1569乳腺癌细胞系中证实了生理效应。外源性棕榈酸酯诱导HER 2/neu阳性乳腺癌细胞功能不同的转录程序。在脂肪生成HER 2/neu阳性SKBR 3细胞系中，棕榈酸酯诱导G2期细胞周期延迟和CHOP依赖性凋亡，以及通过XBP 1和ATF 6部分激活ER应激反应网络。这种反应似乎是HER 2/neu阳性乳腺癌细胞的一般特征，而不是仅过表达HER 2/neu的细胞。外源性棕榈酸酯可降低HER 2和HER 3蛋白水平，而不改变磷酸化，并使HER 2/neu阳性乳腺癌细胞对HER 2靶向治疗曲妥珠单抗治疗敏感。几项研究表明，HER 2、脂肪酸和脂肪酸合成在功能上是相关的。外源性棕榈酸酯部分通过诱导ER应激、降低HER 2表达从而使细胞对曲妥珠单抗敏感来发挥其毒性作用。这些数据提供了进一步的证据，证明HER 2信号传导和脂肪酸代谢是高度整合的过程，可能对疾病的发展和进展很重要。本文的在线版本（doi：10.1186/s12885-016-2611-8）包含补充材料，可供授权用户使用。
HER2/neu-positive breast cancer cells have recently been shown to use a unique Warburg-like metabolism for survival and aggressive behavior. These cells exhibit increased fatty acid synthesis and storage compared to normal breast cells or other tumor cells. Disruption of this synthetic process results in apoptosis. Since the addition of physiological doses of exogenous palmitate induces cell death in HER2/neu-positive breast cancer cells, the pathway is likely operating at its limits in these cells. We have studied the response of HER2/neu-positive breast cancer cells to physiological concentrations of exogenous palmitate to identify lipotoxicity-associated consequences of this physiology. Since epidemiological data show that a diet rich in saturated fatty acids is negatively associated with the development of HER2/neu-positive cancer, this cellular physiology may be relevant to the etiology and treatment of the disease. We sought to identify signaling pathways that are regulated by physiological concentrations of exogenous palmitate specifically in HER2/neu-positive breast cancer cells and gain insights into the molecular mechanism and its relevance to disease prevention and treatment. Transcriptional profiling was performed to assess programs that are regulated in HER2-normal MCF7 and HER2/neu-positive SKBR3 breast cancer cells in response to exogenous palmitate. Computational analyses were used to define and predict functional relationships and identify networks that are differentially regulated in the two cell lines. These predictions were tested using reporter assays, fluorescence-based high content microscopy, flow cytometry and immunoblotting. Physiological effects were confirmed in HER2/neu-positive BT474 and HCC1569 breast cancer cell lines. Exogenous palmitate induces functionally distinct transcriptional programs in HER2/neu-positive breast cancer cells. In the lipogenic HER2/neu-positive SKBR3 cell line, palmitate induces a G2 phase cell cycle delay and CHOP-dependent apoptosis as well as a partial activation of the ER stress response network via XBP1 and ATF6. This response appears to be a general feature of HER2/neu-positive breast cancer cells but not cells that overexpress only HER2/neu. Exogenous palmitate reduces HER2 and HER3 protein levels without changes in phosphorylation and sensitizes HER2/neu-positive breast cancer cells to treatment with the HER2-targeted therapy trastuzumab. Several studies have shown that HER2, FASN and fatty acid synthesis are functionally linked. Exogenous palmitate exerts its toxic effects in part through inducing ER stress, reducing HER2 expression and thereby sensitizing cells to trastuzumab. These data provide further evidence that HER2 signaling and fatty acid metabolism are highly integrated processes that may be important for disease development and progression. The online version of this article (doi:10.1186/s12885-016-2611-8) contains supplementary material, which is available to authorized users.