Differential effects of Hv1 proton channel inhibition on intracellular pH and cell cycle progression of tumorigenic and non-tumorigenic human breast cells. 2D and 3D studies

VENTURA C; LEON I.E; ASUAJE A; ENRIQUE N

Congreso; : LXIII Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica, LXII Reunión Anual de la Sociedad Argentina de Inmunologia (SAIC-SAI-SAFIS); 2018

Metabolic reprogramming of cancer cells conduces to a high production of acidic substances that must be extruded to maintain cell viability. The voltage-gated proton channel (Hv1) mediates highly selective H+ outward currents which prevent the cytoplasmic acidification. In this work, we studied the effect of the proton channel Hv1 inhibition by a guanidine-benzimidazole derivate, ClGBI, in tumorigenic (MCF-7 and MDA-MB-231) and non-tumorigenic (MCF-10A) human breast cells. Our results demonstrated that 10 µM ClGBI reduces the clonogenic capacity of tumorigenic breast cells in a no-reversible way, while this parameter could be reverted in MCF-10A cells after ClGBI removal. This effect was associated with decreased cell viability, both in monolayer as in the 3D cultured, and cell cycle deregulation of tumorigenic cells, which were not observed in the non-tumorigenic MCF-10A cell line. Moreover, our results demonstrated that ClGBI produce a drop of intracellular pH in tumorigenic cells, but not in non-tumorigenic cells. Finally, we demonstrated that tumorigenic breast cells express the amino-terminally truncated isoform of the channel, which was previously descripted in other malignant cells . In summary, our results demonstrated that Hv1 channel could be a therapeutic molecular target to breast cancer disease, since its inhibition preferentially alters proliferation and cell cycle progression of tumorigenic cells, without effects in non-tumorigenic human breast cell lines.