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, 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 alpha 2 beta 1. Cells reached their maximum motility at pH(e) similar to 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, 6.6. It weakened at basic pH,, upon NHE inhibition, or upon blockage of the integrin alpha 2 beta 1. We propose that pH, 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,) or too weak (alkaline pH(e) or NHE inhibition).