Differential expression of the long and truncated Hv1 isoforms in breast‐cancer cells

Metabolic reprogramming of cancer cells results in a high production of acidic substances that must be extruded to maintain tumor‐cell viability. The voltage‐gated proton channel (Hv1) mediates highly selective effluxes of hydronium‐ion (H+) that prevent deleterious cytoplasmic acidification. In the work described here, we demonstrated for the first time that the amino‐terminal–truncated isoform of Hv1 is more highly expressed in tumorigenic breast‐cancer‐cell lines than in nontumorigenic breast cells. With respect to Hv1 function, we observed that pharmacologic inhibition of that channel, mediated by the specific blocker 5‐chloro‐2‐guanidinobenzimidazole, produced a drop in intracellular pH and a decrease in cell viability, both in monolayer and in three‐dimensional cultures, and adversely affected the cell‐cycle in tumorigenic breast cells without altering the cycling of nontumorigenic cells. In conclusion, our results demonstrated that the Hv1 channel could be a potential tool both as a biomarker and as a therapeutic target in breast‐cancer disease. Highlights Tumorigenic breast cells express the N‐terminally truncated isoform of Hv1. Hv1 inhibition decreases pHi and cell viability of tumorigenic human‐breast cells. Hv1 inhibition arrests cell‐cycle of tumorigenic human‐breast cells. Hv1 inhibition does not alter pHi or viability of nontumorigenic breast cells. Hv1 inhibition irreversibly reduces clonogenic capability of tumorigenic breast cells.