Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes
Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes
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DOI：
10.1152/ajpcell.2000.278.4.c676
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发表时间：
2000-04-01
影响因子：
5.5
通讯作者：
Cala, PM
中科院分区：
文献类型：
--
作者：
McLean, LA;Roscoe, J;Cala, PM
与未转化的星形胶质细胞相比，恶性胶质瘤表现出碱性细胞内pH（pH（i））和酸性细胞外pH（pH（e）），尽管代谢H+产生增加。酸性pH（e）限制HCO 3-的可用性，从而减少被动和动态HCO 3-依赖性缓冲。这意味着胶质瘤依赖于动态HCO 3-非依赖性H+缓冲途径，如1型Na+/H+交换器（NHE 1）。在这项研究中，四个快速增殖的胶质瘤表现出显着更多的碱性稳态pH（i）（pH（i）= 7.31-7.48）比正常的星形胶质细胞（pH（i）= 6.98），并增加从酸化的恢复率，在名义上的CO2/HCO 3-无条件。在没有CO2/HCO 3-的情况下抑制NHE 1导致胶质瘤明显酸化，而正常星形胶质细胞不受影响。当悬浮于CO2/HCO 3-介质中时，星形胶质细胞pH（i）增加，但胶质瘤pH（i）意外地酸化，表明存在HCO 3-依赖性酸加载途径。来自胶质瘤的NHE 1 cDNA的核苷酸测序表明，遗传改变不是NHE 1功能改变的原因。这些数据表明，NHE 1活性在胶质瘤中显著升高，并可能为肿瘤选择性治疗的发展提供有用的靶点。
Malignant gliomas exhibit alkaline intracellular pH (pH(i)) and acidic extracellular pH (pH(e)) compared with nontransformed astrocytes, despite increased metabolic H+ production, The acidic pH(e) limits the availability of HCO3-, thereby reducing both passive and dynamic HCO3--dependent buffering. This implies that gliomas are dependent upon dynamic HCO3--independent H+ buffering pathways such as the type 1 Na+/H+ exchanger (NHE1). In this study, four rapidly proliferating gliomas exhibited significantly more alkaline steady-state pH(i) (pH(i) = 7.31-7.48) than normal astrocytes (pH(i) = 6.98), and increased rates of recovery from acidification, under nominally CO2/HCO3--free conditions. Inhibition of NHE1 in the absence of CO2/HCO3- resulted in pronounced acidification of gliomas, whereas normal astrocytes were unaffected. When suspended in CO2/HCO3- medium astrocyte pH(i) increased, yet glioma pH(i) unexpectedly acidified, suggesting the presence of an HCO3--dependent acid loading pathway, Nucleotide sequencing of NHE1 cDNA from the gliomas demonstrated that genetic alterations were not responsible for this altered NHE1 function. The data suggest that NHE1 activity is significantly elevated in gliomas and may provide a useful target for the development of tumor-selective therapies.