The inhibition of voltage-gated H+ channel (HVCN1) induces acidification of leukemic Jurkat T cells promoting cell death by apoptosis

ASUAJE AGUSTIN; SMALDINI P; PEDRO MARTIN; ENRIQUE NICOLÁS; ORLOWSKI ALEJANDRO; AIELLO ALEJANDRO; GONZALEZ LEON CARLOS; DOCENA GUILLERMO; MILESI VERÓNICA

PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY

SPRINGER

Lugar: Berlin; Año: 2017 vol. 469 p. 251 - 261

0031-6768

Cellular energetic deregulation is widely known to produce an overproduction of acidic species in 27 cancer cells. This acid overload must be counterbalanced with a high rate of H+ extrusion mechanism to 28 maintain cell viability. In this sense, many H+ transporters have been reported to be crucial for cell survival and 29 proposed as anti-neoplastic target. By the way, Voltage Gated Proton Channels (Hv1) mediate high selective H+ 30 outward currents, capable of compensate acid burden in brief periods of time. This structure is canonicaly 31 described acting as NADPHOx counterbalance in ROS production. In this work we show that inhibition of Hv1 32 channels by Zn2+ and the more selective blocker 5-chloro-2-guanidinobenzimidazole (ClGBI) progressively 33 decreases intracellular pH in resting conditions in leukemic Jurkat T cells, aside from heavy acid loads 34 compensation. Our results reveal how blockade produces an immediate change in pHi baseline, that further 35 progress into deliberate intracellular acidification and later apoptosis mediated cell death. Altogether, this work 36 points out a new role for this channel in cancer biology.