Abstract
BackgroundRecent studies demonstrate that interstitial inorganic phosphate is significantly elevated in the breast cancer microenvironment as compared to normal tissue. In addition it has been shown that breast cancer cells express high levels of the NaPi-IIb carrier (SLC34A2), suggesting that this carrier may play a role in breast cancer progression. However, the biochemical behavior of inorganic phosphate (Pi) transporter in this cancer type remains elusive.MethodsIn this work, we characterize the kinetic parameters of Pi transport in the aggressive human breast cancer cell line, MDA-MB-231, and correlated Pi transport with cell migration and adhesion.ResultsWe determined the influence of sodium concentration, pH, metabolic inhibitors, as well as the affinity for inorganic phosphate in Pi transport. We observed that the inorganic phosphate is dependent on sodium transport (K0,5 value = 21.98 mM for NaCl). Furthermore, the transport is modulated by different pH values and increasing concentrations of Pi, following the Michaelis-Menten kinetics (K0,5 = 0.08 mM Pi). PFA, monensin, furosemide and ouabain inhibited Pi transport, cell migration and adhesion.ConclusionsTaken together, these results showed that the uptake of Pi in MDA-MB-231 cells is modulated by sodium and by regulatory mechanisms of intracellular sodium gradient.General Significance: Pi transport might be regarded as a potential target for therapy against tumor progression.
Highlights
Phosphorus is an essential element found in all forms of life
We determined the influence of sodium concentration, pH, metabolic inhibitors, as well as the affinity for inorganic phosphate in Pi transport
phosphonoformic acid (PFA), monensin, furosemide and ouabain inhibited Pi transport, cell migration and adhesion. These results showed that the uptake of Pi in MDA-MB-231 cells is modulated by sodium and by regulatory mechanisms of intracellular sodium gradient
Summary
Phosphorus is an essential element found in all forms of life. In mammals, it is obtained from the diet in the anionic form of Pi (H2PO-4 or HPO-4) through absorption in the small intestine [1]. Inorganic phosphate (Pi) plays a critical role in several cellular processes such as energy metabolism, either in the form of ATP by the energy transfer mechanism, or in its free form as substrates for intermediates of metabolic pathways. Several inorganic phosphate transporters have been described and can be classified into three different protein families denoted NaPi-I, NaPi-II and NaPi-III. NaPi-II (SLC34) is a sodium-dependent phosphate transporter that carries the phosphate in its monovalent form. It is further classified in the following subfamilies: NaPi-IIa (SLC34A1), NaPi-IIb (SLC34A2), and NaPi-IIc (SLC34A3); NaPi-IIb is found in breast cells [1,5,6,7,8]. The type III, NaPi-III (SLC20) transporters family, comprises proteins responsible for a sodium-dependent phosphate transport in its monovalent form. The biochemical behavior of inorganic phosphate (Pi) transporter in this cancer type remains elusive
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