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首页> 外文期刊>Cellular Oncology: Analytical Cellular Pathology >Altered Ca2+-Homeostasis of Cisplatin-Treated and Low Level Resistant Non-Small-Cell and Small-Cell Lung Cancer Cells
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Altered Ca2+-Homeostasis of Cisplatin-Treated and Low Level Resistant Non-Small-Cell and Small-Cell Lung Cancer Cells

机译：顺铂治疗和低水平耐药的非小细胞和小细胞肺癌细胞的钙离子稳态改变。

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Background: Chemotherapy often leads to encouraging responses in lung cancer. But, in the course of the treatment, resistance to chemotherapy ultimately limits the life expectancy of the patient. We aimed at investigating if treatment with cisplatin alters the intracellular Ca2+-homeostasis of lung cancer cells and how this may be related to cisplatin resistance.Methods: The squamous cell lung carcinoma cell line EPLC M1 and the small cell lung cancer cell line H1339 were exposed to cisplatin analogue to thein vivopharmacokinetics. Changes in the cytoplasmic Ca2+-concentration ([Ca2+]c) were recorded using fluorescence microscopy. Protein expression was quantified using immuno-fluorescence and Western Blot analysis. Changes in gene expression were accomplished by small-interfering (si) RNA techniques.Results: Four “cycles” of cisplatin led to low level resistance in EPLC and H1339 cells. In the low level resistant cell clones, the Ca2+-content of the endoplasmic reticulum (ER) was decreased. In low level resistant EPLC cells, this was correlated with an increased expression of the inositol-1,4,5-trisphosphate receptor (IP3R). Inhibiting the increased expression of IP3R using siRNA, the low level resistance could be reversed. In low level resistant H1339 cells, the decreased Ca2+-content of the ER was correlated with a decreased expression of sarco/endoplasmic reticulum Ca2+-ATPases (SERCA). Decreasing the expression of SERCA in naïve H1339 cells resulted in low level cisplatin resistance.Conclusion: We conclude that cisplatin therapy leads to a decreased Ca2+-content of the ER thereby inducing low level resistance. This is caused by upregulation of the IP3R in EPLC and decreased expression of SERCA in H1339 cells.
机译：背景：化学疗法通常会导致令人鼓舞的肺癌反应。但是，在治疗过程中，对化学疗法的抗性最终限制了患者的预期寿命。我们的目的是研究用顺铂治疗是否会改变肺癌细胞的细胞内Ca2 +稳态及其与顺铂耐药性的关系。方法：暴露鳞状细胞肺癌细胞EPLC M1和小细胞肺癌细胞H1339顺铂类似物在体内的药代动力学。使用荧光显微镜记录细胞质中Ca2 +浓度（[Ca2 +] c）的变化。使用免疫荧光和蛋白质印迹分析定量蛋白质表达。基因表达的变化通过小干扰（si）RNA技术完成。结果：顺铂的四个“周期”导致EPLC和H1339细胞的低水平耐药性。在低水平抗性细胞克隆中，内质网（ER）的Ca2 +含量降低。在低水平抗性EPLC细胞中，这与肌醇-1,4,5-三磷酸受体（IP3R）的表达增加有关。使用siRNA抑制IP3R的表达增加，可以逆转低水平的抗性。在低水平耐药的H1339细胞中，ER的Ca2 +含量降低与肌/内质网Ca2 + -ATPases（SERCA）的表达降低有关。结论：顺铂治疗可导致ER的Ca2 +含量降低，从而诱导低水平的耐药性。这是由于EPLC中IP3R的上调和H1339细胞中SERCA的表达降低所致。

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