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

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 HCO^-/₃, thereby reducing both passive and dynamic HCO^-/₃-dependent buffering. This implies that gliomas are dependent upon dynamic HCO^-/₃- 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/HCO^-/₃-free conditions. Inhibition of NHE1 in the absence of CO₂/HCO^-/₃ resulted in pronounced acidification of gliomas, whereas normal astrocytes were unaffected. When suspended in CO₂/HCO^-/₃ medium astrocyte ph(i) increased, yet glioma pH(i) unexpectedly acidified, suggesting the presence of an HCO^-/₃-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.