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Requirement of the Na⁺/H⁺ Exchanger for Tumor Growth¹

Department of Medicine and Medical Biophysics, Ontario Cancer Institute and University of Toronto, Toronto, Ontario, M4X 1K9 [D. R., D. S-N., I. T.], and Department of Cell Biology and Biochemistry, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, [S. G.] Canada

The Na⁺/H⁺ exchanger is involved in a variety of cellular processes, including regulation of intracellular pH and possibly the control of cell growth and proliferation. To study the role of the Na⁺/H⁺ exchanger in tumor growth, human sodium proton exchanger-deficient (HSPD) mutants were derived from the human bladder carcinoma cell line MGH-U1 (EJ) by the proton suicide selection technique (J. Pouyssegur et al., Proc. Natl. Acad. Sci. USA, 81: 4833–4837, 1984). The HSPD cells were 40% larger and contained 70% more DNA than the parental cells. They were unable to grow in vitro in the absence of bicarbonate at pH <7.0, whereas the parental cells grew well at pH 6.6. This difference in acid sensitivity was abolished in the presence of bicarbonate. In contract to the parental MGH-U1 cells, the Na⁺/H⁺-deficient HSPD cells either failed to grow tumors, or showed severely retarded tumor growth when implanted into immune-deprived mice. This difference in tumor growth was not attributed to differences in cell size and DNA content, because Na⁺/H⁺ exchange-competent large cells (HLC), derived during the same proton suicide selection process as the HSPD cells, grew tumors at a rate close to that of the parental cells. Cells derived from the few tumors which grew after implantation of HSPD mutant cells were revertants which had regained Na⁺/H⁺ activity. HSPD cells also failed to form spheroids in culture, and the only spheroid formed consisted of revertant cells which had regained both Na⁺/H⁺ exchange activity and tumorigenic capacity. These results suggest that the Na⁺/H⁺ exchanger is important for tumor growth.

¹ This work was supported by Grant CA 36913 from the NIH, and by a research grant from the National Cancer Institute of Canada and from the Medical Research Council of Canada.

² Recipient of a research studentship from the National Cancer Institute of Canada.

³ To whom requests for reprints should be addressed.

Received 3/11/88. Revised 7/ 5/88. Accepted 10/ 4/88.

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