Migration of human melanoma cells depends on extracellular pH and Na+/H+ exchange

Their glycolytic metabolism imposes an increased acid load upon tumour cells. The surplus protons are extruded by the Na⁺/H⁺ exchanger (NHE) which causes an extracellular acidification. It is not yet known by what mechanism extracellular pH (pH_e) and NHE activity affect tumour cell migration and thus metastasis. We studied the impact of pH_e and NHE activity on the motility of human melanoma (MV3) cells. Cells were seeded on/in collagen I matrices. Migration was monitored employing time lapse video microscopy and then quantified as the movement of the cell centre. Intracellular pH (pH_i) was measured fluorometrically. Cell–matrix interactions were tested in cell adhesion assays and by the displacement of microbeads inside a collagen matrix. Migration depended on the integrin α2β1. Cells reached their maximum motility at pH_e～7.0. They hardly migrated at pH_e 6.6 or 7.5, when NHE was inhibited, or when NHE activity was stimulated by loading cells with propionic acid. These procedures also caused characteristic changes in cell morphology and pH_i. The changes in pH_i, however, did not account for the changes in morphology and migratory behaviour. Migration and morphology more likely correlate with the strength of cell–matrix interactions. Adhesion was the strongest at pH_e 6.6. It weakened at basic pH_e, upon NHE inhibition, or upon blockage of the integrin α2β1. We propose that pH_e and NHE activity affect migration of human melanoma cells by modulating cell–matrix interactions. Migration is hindered when the interaction is too strong (acidic pH_e) or too weak (alkaline pH_e or NHE inhibition).