VOLTAGE GATED PROTON CHANNELS AS ESSENTIAL STRUCTURE IN LEUKEMIC JURKAT T CELL PH HOMEOSTASIS AND SURVIVAL

ENRIQUE NICOLAS; AIELLO, ALEJANDRO; AGUSTÍN ASUAJE; ORLOWSKI, ALEJANDRO; MILESI VERONICA; MARTIN PEDRO; DOCENA, GUILLERMO

Bertinoro

Congreso; International Society of Cancer Metabolism 4th Annual Meeting; 2017

International Society of Cancer Metabolism

Hv1 are voltage- activated low conductance and highly selective proton channels. Localized in the cell membrane, they are able to compensate intracellular acidification by carrying out H+ outward currents. Recently Hv1 channel was found overexpressed in different human tumors, mostly related with metastasis and poor prognosis. Knowing that cancer cells have a metabolic deregulation that promotes the increase of intracellular acidic species (Warburg effect), Hv1 channels might allow a quick compensation of cellular proton production and thus give cancer cells an advantage to prevent the acidification related-cell death. Therefore, Hv1 inhibition could be useful to induce tumoral cells death.We focus our study on Hv1 channels of leukemic Jurkat T cells and their role over pHi homeostasis. We found that short term Hv1 blockade by Zn2+ 1mM and ClGBI 0.2 mM significantly decreased basal pHi within 15 min. (pHi= -0,210±0,023 and -0,115±0,0101, respectively) and recovery rate after a propionic acid pulse (J= 0.020±0.004 and 0.021±0.004 H+ mM/min, respectively) in sodium free extracellular solutions. Although with different magnitude, these results were reproduced in physiological sodium by blocking Hv1 with ClGBI 0.2 mM (pHi= -0.048±0.021 and 0.045±0.029 H+ mM/min); indicating that, even in a condition where other well-known proton transporters as the NHE exchanger could be functional, Hv1 channel is relevant in pHi homeostasis of these cells. Moreover, long term Hv1 blockade with ClGBI (2, 17 and 48hs) in culture conditions showed a significant pH drop, assessed by flow cytometry, time and concentration dependent (Two Way ANOVA, p