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

Abstract

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 CO(2)/HCO(-)(3)-free conditions. Inhibition of NHE1 in the absence of CO(2)/HCO(-)(3) resulted in pronounced acidification of gliomas, whereas normal astrocytes were unaffected. When suspended in CO(2)/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.

Differential gene expression profiles of gastric cancer cells established from primary tumour and malignant ascites

“…Dopa decarboxylase (DDC) is responsible for the synthesis of the key neurotransmitters dopamine and serotonin, and is frequently expressed in neuroblastoma and small cell carcinoma of the lung (North and Du, 1998;Gilbert et al, 1999). Sodium/ hydrogen exchanger isoform 1, is activated more in malignant gliomas than nontransformed astrocytes, and malignant gliomas display altered pH regulation (Lagana et al, 2000;McLean et al, 2000). LMO7 in gastric cancer has not been dealt with in any reports, but another isoform, LMO4 (a transcriptional regulator) inhibits differentiation of mammary epithelial cells in vitro and is GenBank accession number, fold change verified by high-density oligonucleotide array and Northern blot, and one representative function of the genes as previously reported are shown.…”

BAX inhibitor-1 enhances cancer metastasis by altering glucose metabolism and activating the sodium-hydrogen exchanger: the alteration of mitochondrial function

“…The ubiquitously expressed Na þ /H þ exchanger isoform, sodium hydrogen exchanger (NHE1), also contributes to this acidic environment (Plopper et al, 1995). NHE1 activity is important for many tumor cells (Lagarde et al, 1988;Rotin et al, 1989;McLean et al, 2000). Insufficient and/ or inefficient tumor vascularization leads to diminished O 2 supply so that tumor cell metabolism is mostly glycolytic (Helmlinger et al, 2002).…”

Effect of NHE1 antisense gene transfection on the biological behavior of SGC-7901 human gastric carcinoma cells

“…However, further studies are needed to determine whether or not the intervention of antisense NHE1 gene can decrease type 1 Na + /H + exchanger of membranous ion exchange protein in gastric carcinoma cells and reverse the malignant phenotypes. Therefore, in the present study, the purpose of transfection of antisense NHE1 gene into human gastric carcinoma cell line [19][20][21][22][23][24][25][26] . The enhancement of Na + -H + exchange by tumor cells, caused by increasing the quantitative distribution of NHE1 on the cell membrane, is the major molecular mechanism in the regulation of pH i in tumor cells.…”