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 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.
| Original language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Cell Physiology |
| Volume | 278 |
| Issue number | 4 47-4 |
| State | Published - 2000 |
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Keywords
- Astrocytomas
- Glioblastomas
- Sodium/hydrogen antiport
- Tumor pH
ASJC Scopus subject areas
- Clinical Biochemistry
- Cell Biology
- Physiology
- Physiology (medical)
Cite this
Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes. / McLean, Lee Anne; Roscoe, Jane; Jørgensen, Nanna K.; Gorin, Fredric A; Cala, Peter M.
In: American Journal of Physiology - Cell Physiology, Vol. 278, No. 4 47-4, 2000.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes
AU - McLean, Lee Anne
AU - Roscoe, Jane
AU - Jørgensen, Nanna K.
AU - Gorin, Fredric A
AU - Cala, Peter M
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
KW - Astrocytomas
KW - Glioblastomas
KW - Sodium/hydrogen antiport
KW - Tumor pH
UR - http://www.scopus.com/inward/record.url?scp=0034129031&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034129031&partnerID=8YFLogxK
M3 - Article
C2 - 10751317
AN - SCOPUS:0034129031
VL - 278
JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
SN - 1931-857X
IS - 4 47-4
ER -