Phosphoinositide 3-kinase is involved in the tumor-specific activation of human breast cancer cell Na+/H+ exchange, motility, and invasion induced byserum deprivation

Whereas the tumor acidic extracellular pH plays a crucial role in the invas ive process, the mechanism(s) behind this acidification, especially in low nutrient conditions, are unclear. The regulation of the Na+/H+ exchanger (N HE) and invasion by serum deprivation were studied in a series of breast ep ithelial cell lines representing progression from non-tumor to highly metas tatic cells. Whereas serum deprivation reduced lactate production in all th ree cells lines, it inhibited NHE activity in the non-tumor cells and stimu lated it in the tumor cells with a larger stimulation in the metastatic cel ls. The stimulation of NHE in the tumor cell lines was the result of an inc reased affinity of the internal H+ regulatory site of the NHE without chang es in sodium kinetics or expression, Serum deprivation conferred increased cell motility and invasive ability that were abrogated by specific inhibiti on of the NHE, Inhibition of phosphoinositide 3-kinase by overexpression of a dominant-negative mutant or wortmannin incubation inhibited NHE activity and invasion in serum replete conditions while potentiating the serum depr ivation-dependent activation of the NHE and invasion. These results indicat e that the up-regulation of the NHE by a phosphoinositide 3-kinase-dependen t mechanism plays an essential role in increased tumor cell invasion induce d by serum deprivation.