Elevated extracellular inorganic phosphate inhibits ecto‐phosphatase activity in breast cancer cells: Regulation by hydrogen peroxide

For cells to obtain inorganic phosphate, ectoenzymes in the plasma membrane, which contain a catalytic site facing the extracellular environment, hydrolyze phosphorylated molecules. In this study, we show that increased Pi levels in the extracellular environment promote a decrease in ecto‐phosphatase activity, which is associated with Pi‐induced oxidative stress. High levels of Pi inhibit ecto‐phosphatase because Pi generates H2O2. Ecto‐phosphatase activity is inhibited by H2O2, and this inhibition is selective for phospho‐tyrosine hydrolysis. Additionally, it is shown that the mechanism of inhibition of ecto‐phosphatase activity involves lipid peroxidation. In addition, the inhibition of ecto‐phosphatase activity by H2O2 is irreversible. These findings have new implications for understanding ecto‐phosphatase regulation in the tumor microenvironment. H2O2 stimulated by high Pi inhibits ecto‐phosphatase activity to prevent excessive accumulation of extracellular Pi, functioning as a regulatory mechanism of Pi variations in the tumor microenvironment.