Redox Regulation of Phosphatase and Tensin Homolog by Bicarbonate and Hydrogen Peroxide: Implication of Peroxymonocarbonate in Cell Signaling

Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) signaling pathway. Notably, its active site contains a cysteine residue that is susceptible to oxidation by hydrogen peroxide (H₂O₂). This oxidation inhibits the Phosphatase function of PTEN, critically contributing to the activation of the PI3K/Akt pathway. Upon the stimulation of cell surface receptors, the activity of NADPH Oxidase (NOX) generates a transient amount of H₂O₂, serving as a mediator in this pathway by oxidizing PTEN. The mechanism underlying this oxidation, occurring despite the presence of highly efficient and abundant cellular oxidant-protecting and reducing systems, continues to pose a perplexing conundrum. Here, we demonstrate that the presence of bicarbonate (HCO₃^-) promoted the rate of H₂O₂-mediated PTEN oxidation, probably through the formation of peroxymonocarbonate (HCO₄^-), and consequently potentiated the phosphorylation of Akt. Acetazolamide (ATZ), a Carbonic Anhydrase (CA) inhibitor, was shown to diminish the oxidation of PTEN. Thus, CA can also be considered as a modulator in this context. In essence, our findings consolidate the crucial role of HCO₃^- in the redox regulation of PTEN by H₂O₂, leading to the presumption that HCO₄^- is a signaling molecule during cellular physiological processes.