Role of voltage-gated proton channel (Hv1) in cancer biology

Abstract

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.

Keywords: Hv1; cancer; channel; metastasis (cancer metastasis); oncology; pH; proton; tumor.

FIGURE 1

Hv1 reflects molecular arrangements that sustain its voltage-dependent conduction. (A) Truncated mHv1 lacking its N and C cytoplasmic terminal domains (PDB code: 3WKV, Takeshita et al., 2014) simulated in a POPC membrane bathed with a 150 mM NaCl salt solution for 0.5 ns (36141 atoms). In white: apolar residues, in green: polar residues. It is shown in blue (from up to down) three arginines related to the S4 domain, from up-to-down: Arg205 (R1), Arg 208 (R2) and Arg 2011 (R3), in red Asp112 in S1 and Asp174 in S3, and waters in VDW representation. (B) Full length mHv1 in dimer form, built from the best model scored of 10000 N terminal models by using Rosetta Ab initio relax application (Bradley et al., 2005), a truncated hHv1 lacking N and C terminal domains (PDB code: 5OQK, Bayrhuber et al., 2019) and the coiled-coil dimerization C terminal domain (PDB code: 3VMX, Fujiwara et al., 2012). Full length hHv1 was duplicated and positioned each monomer in front of their S1-S4 interphase following cross-linking and dimeric data (Lee et al., 2008; Mony et al., 2020) and simulated for 1 ns embedded in POPC bathed with an aqueous saline solution of 150 mM (123017 atoms). (C) Top view of the full length mHv1 S1-S4 dimer interface.

FIGURE 2

Structure of the Hv1 channel and molecular determinants of Zn²⁺ and Guanidine derivatives binding sites. The molecular determinants in the interaction of the protein with the classical inhibitors zinc ion and guanidine derivatives are pointed in (A) the monomeric channel cartoon, indicating in what species were discovered the interaction with the chemical compounds and, (B) in the sequence alignment between long and short Hv1 isoforms.

FIGURE 3

Elements of the tumor microenvironment and how Hv1 channel is crucial to sustain some malignant features in cancer. Tumoral microenvironment is constituted by several cellular elements, where immune system cells are key to maintain the tumoral microenvironment conditions to promote cancer cell development. In some of these cellular elements, the Hv1 channel has been shown to possess an important role. Proton extrusion through Hv1 promotes local acidification of the TME, which in turn, has been shown to induce the activation of extracellular matrix degrading proteases favoring cancer cell migration. On the other hand, MDSC are strongly immunosuppressive, preventing and interfering with tumor elimination by T-cells. This immunosuppression is led by ROS production via NOX2 enzymatic complex, a process that is sustained thanks to the functional coupling between NOX2 and Hv1 channel. Moreover, cancer cells release tumoral factors that maintain the features of the tumoral microenvironment. Examples of these are VEGF, HIF, GM-CSF, TNF-α, IL-12, IL-10, TGF-β. GM-CSF recruits MDSC to the tumoral microenvironment and maintains its strongly immunosuppressive phenotype.

FIGURE 4

The intervention of the Hv1 function as a feasible therapeutic strategy for circumventing the TME. The presence of the Hv1 channel in cancer cells could be helpful to control the cytosolic pH. Once blocked, intracellular acidification could be harmful for tumors. On the other hand, in MDSC, Hv1 allows the sustained production of ROS, which give rise to the immunosuppressive function of MDSC. Then, the inhibition of Hv1 could diminish its immunosuppressive function. Both effects together could induce a decrease in tumor size.