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1 Physiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
* To whom correspondence should be addressed. E-mail: Souad.Sennoune{at}ttuhsc.edu.
Tumor cells thrive in a hypoxic micro-environment with an acidic extracellular pH. In order to survive in this harsh environment, tumor cells must exhibit a dynamic cytosolic pH (pHcyt) regulatory system. We hypothesize that vacuolar H+-ATPases (V-ATPases) that normally reside in acidic organelles are also located at the cell surface, thus regulating pHcyt and exacerbating the migratory ability of metastatic cells. Immunocytochemical data revealed for the first time that V-ATPase is located at the plasma membrane (herein referred as pmV-ATPase) of human breast cancer cells: prominent in the highly metastatic and incospicuous in the lowly metastatic cells. The V-ATPase activities in isolated plasma membranes were greater in highly than in lowly metastatic cells. The proton fluxes via V-ATPase evaluated by fluorescence spectroscopy in living cells were greater in highly than in lowly metastatic cells. Interestingly, lowly metastatic cells preferentially used the ubiquitous Na+/H+ exchanger and HCO3--based H+-transporting mechanisms, whereas highly metastatic cells used pmV-ATPases. The highly metastatic cells were more invasive/migratory than the lowly metastatic cells. V-ATPase inhibitors decreased the invasion/migration in the highly metastatic cells. Altogether, these data indicate that V-ATPases located at the plasma membrane are involved in the acquisition of a more metastatic phenotype.
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