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J Biol Chem, Vol. 275, Issue 8, 5361-5369, February 25, 2000
From the Whereas the tumor acidic extracellular pH plays a
crucial role in the invasive process, the mechanism(s) behind this
acidification, especially in low nutrient conditions, are unclear. The
regulation of the Na+/H+ exchanger (NHE)
and invasion by serum deprivation were studied in a series of breast
epithelial cell lines representing progression from non-tumor to highly
metastatic cells. Whereas serum deprivation reduced lactate production
in all three cells lines, it inhibited NHE activity in the non-tumor
cells and stimulated it in the tumor cells with a larger stimulation in
the metastatic cells. The stimulation of NHE in the tumor cell lines
was the result of an increased affinity of the internal H+
regulatory site of the NHE without changes in sodium kinetics or
expression. Serum deprivation conferred increased cell motility and
invasive ability that were abrogated by specific inhibition 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 deprivation-dependent activation of the NHE and
invasion. These results indicate that the up-regulation of the NHE by a phosphoinositide 3-kinase-dependent mechanism plays an
essential role in increased tumor cell invasion induced by serum deprivation.
Phosphoinositide 3-Kinase Is Involved in the Tumor-specific
Activation of Human Breast Cancer Cell Na+/H+
Exchange, Motility, and Invasion Induced by Serum Deprivation*
§,,,
,
Department of General and Environmental
Physiology, University of Bari, the ¶ Laboratory of Experimental
Oncology, Oncology Institute of Bari, 70126 Bari, Italy, and the
Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum,
INF 242, Heidelberg, Germany
*
This work was supported by Consiglio Nazionale delle
Ricerche Grant 97.00592.CT11.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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