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Regulation of Intracellular pH in Tumor Cell Lines: Influence of Microenvironmental Conditions¹

Departments of Medicine and Medical Biophysics, Ontario Cancer Institute and University of Toronto, Toronto, Ontario M4X 1K9, Canada

The effect of microenvironmental factors on the regulation of intracellular pH (pH_i) in MGH U1 cells and EMT-6 cells was studied using the fluorescent pH probe 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxy-fluorescein. Na⁺/H⁺ exchange and Na⁺-dependent Cl^–/HCO^–₃ exchange were found to be present in both cell types. The activity of both exchangers was dependent on pH_i, with low levels of activity at neutral pH and an increase in activity as pH_i fell. The level of extracellular pH (pH_e) also influenced the operation of the exchangers, with a fall in activity as pH_e was reduced over the range 7.4–6.6. This effect was more marked for the Na⁺-dependent Cl^–/HCO^–₃ exchanger than for the Na⁺/H⁺ antiporter, suggesting that under conditions of reduced pH_e the Na⁺/H⁺ antiporter is the major mechanism for regulation of pH_i. Neither 6 h of radiobiological hypoxia nor variations in the extracellular [Ca²⁺] over the range 1–6 mM had an effect on the regulation of pH_i, while extracellular lactate (5–10 mM) caused a small, concentration-dependent decrease in the combined activity of both exchangers. We conclude that under the microenvironmental conditions found in some regions of tumors, Na⁺/H⁺ exchange may be the major method of regulation of pH_i.

¹ Supported by Grant CA51033 from the NIH.

² M. J. B. is supported by the Medical Research Council of Canada.

³ To whom requests for reprints should be addressed, at Room 741, Ontario Cancer Institute, 500 Sherbourne Street, Toronto, ON M4X 1K9, Canada.

Received 2/19/92. Accepted 6/ 3/92.

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