Significance Immunosuppression by myeloid-derived suppressor cells (MDSC), especially near tumor surfaces, involves the extracellular production of reactive oxygen species (ROS). ROS generation in MDSC occurs during the oxidation of NADPH to NADP+, which NOX2 catalyzes. ROS react with the T cell receptor complex, abolishing the antigen presentation, which blocks the immune system elimination of the tumor cells. Extrusion of protons from MDSC by voltage-gated proton channel (H v 1) sustains ROS production. Here, we demonstrate the expression of H v 1 in mouse MDSC. In this way, H v 1 present in MDSC becomes a potential cancer therapeutic target since its inhibition seems to diminish immunosuppression activity in the tumoral microenvironment, allowing cancer cells to be attacked by the immune system.

Aquaporins (AQPs) are small transmembrane tetrameric proteins that facilitate water, solute and gas exchange. Their presence has been extensively reported in the biological membranes of almost all living organisms. Although their discovery is much more recent than ion transport systems, different biophysical approaches have contributed to confirm that permeation through each monomer is consistent with closed and open states, introducing the term gating mechanism into the field. The study of AQPs in their native membrane or overexpressed in heterologous systems have experimentally demonstrated that water membrane permeability can be reversibly modified in response to specific modulators. For some regulation mechanisms, such as pH changes, evidence for gating is also supported by high-resolution structures of the water channel in different configurations as well as molecular dynamics simulation. Both experimental and simulation approaches sustain that the rearrangement of conserved residues contributes to occlude the cavity of the channel restricting water permeation. Interestingly, specific charged and conserved residues are present in the environment of the pore and, thus, the tetrameric structure can be subjected to alter the positions of these charges to sustain gating. Thus, is it possible to explore whether the displacement of these charges (gating current) leads to conformational changes? To our knowledge, this question has not yet been addressed at all. In this review, we intend to analyze the suitability of this proposal for the first time.

The acid-base characteristics of tumor cells and the other elements that compose the tumor microenvironment have been topics of scientific interest in oncological research. There is much evidence confirming that pH conditions are maintained by changes in the patterns of expression of certain proton transporters. In the past decade, the voltage-gated proton channel (Hv1) has been added to this list and is increasingly being recognized as a target with onco-therapeutic potential. The Hv1 channel is key to proton extrusion for maintaining a balanced cytosolic pH. This protein-channel is expressed in a myriad of tissues and cell lineages whose functions vary from producing bioluminescence in dinoflagellates to alkalizing spermatozoa cytoplasm for reproduction, and regulating the respiratory burst for immune system response. It is no wonder that in acidic environments such as the tumor microenvironment, an exacerbated expression and function of this channel has been reported. Indeed, multiple studies have revealed a strong relationship between pH balance, cancer development, and the overexpression of the Hv1 channel, being proposed as a marker for malignancy in cancer. In this review, we present data that supports the idea that the Hv1 channel plays a significant role in cancer by maintaining pH conditions that favor the development of malignancy features in solid tumor models. With the antecedents presented in this bibliographic report, we want to strengthen the idea that the Hv1 proton channel is an excellent therapeutic strategy to counter the development of solid tumors.