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Glioblastoma cancer stem cell lines express functional acid sensing ion channels ASIC1a and ASIC3

机译:胶质母细胞瘤癌症干细胞系表达功能性酸敏感离子通道ASIC1a和ASIC3

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摘要

Acidic microenvironment is commonly observed in tumour tissues, including glioblastoma (GBM), the most aggressive and lethal brain tumour in adults. Acid sensing ion channels (ASICs) are neuronal voltage-insensitive sodium channels, which are sensors of extracellular protons. Here we studied and functionally characterized ASICs in two primary glioblastoma stem cell lines as cell culture models. We detected transcripts of the ACCN2 and ACCN3 genes, coding for ASIC1 and ASIC3, respectively, but not transcripts of ACCN1 (coding for ASIC2). Available microarray data confirmed that ACCN1 is downregulated in glioma. Western blotting confirmed expression of ASIC1 and ASIC3, the most proton-sensitive ASICs, in both GBM cell lines. We characterized ASICs functionally using whole-cell patch clamp and detected different types of acid-sensitive currents. Some of these currents had kinetics typical for ASICs and were sensitive to specific toxin inhibitors of ASIC1a or ASIC3, demonstrating that the GBM cell lines express functional ASIC1a and ASIC3 that may enable GBM cells to sensitively detect extracellular pH in a tumour tissue. Microarray data revealed that expression of ACCN2 and ACCN3 is associated with improved survival of patients suffering from gliomas, suggesting that preserved susceptibility to extracellular pH may impair tumour growth.
机译:酸性微环境通常在肿瘤组织中观察到,其中包括成胶质细胞瘤(GBM),它是成年人中最具侵袭性和致死性的脑肿瘤。酸感应离子通道(ASICs)是神经元电压不敏感的钠通道,是细胞外质子的传感器。在这里,我们研究了两种原始胶质母细胞瘤干细胞系中的ASICs并对其进行了功能表征,以此作为细胞培养模型。我们检测到分别编码ASIC1和ASIC3的ACCN2和ACCN3基因的转录本,但未检测到ACCN1(编码ASIC2)的转录本。现有的微阵列数据证实了胶质瘤中ACCN1的表达下调。 Western印迹证实了两种GBM细胞系中对质子最敏感的ASIC1和ASIC3的表达。我们使用全细胞膜片钳对ASIC进行功能表征,并检测到不同类型的酸敏感电流。这些电流中的一些具有ASIC特有的动力学,并且对ASIC1a或ASIC3的特定毒素抑制剂敏感,表明GBM细胞系表达功能性ASIC1a和ASIC3,这些功能可能使GBM细胞能够敏感地检测肿瘤组织中的细胞外pH。基因芯片数据显示,ACCN2和ACCN3的表达与神经胶质瘤患者的生存期延长有关,这表明保留的对细胞外pH的敏感性可能会损害肿瘤的生长。

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