Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes

Abstract

Malignant gliomas exhibit alkaline intracellular pH (pHi) and acidic extracellular pH (pHe) compared with nontransformed astrocytes, despite increased metabolic H+ production. The acidic pHe limits the availability of[Formula: see text], thereby reducing both passive and dynamic [Formula: see text]-dependent buffering. This implies that gliomas are dependent upon dynamic[Formula: see text]-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 pHi(pHi = 7.31–7.48) than normal astrocytes (pHi = 6.98), and increased rates of recovery from acidification, under nominally CO2/[Formula: see text]-free conditions. Inhibition of NHE1 in the absence of CO2/[Formula: see text] resulted in pronounced acidification of gliomas, whereas normal astrocytes were unaffected. When suspended in CO2/[Formula: see text] medium astrocyte pHi increased, yet glioma pHi unexpectedly acidified, suggesting the presence of an[Formula: see text]-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.