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

  • Ion channels, receptors and transporters
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Abstract

Cellular energetic deregulation is widely known to produce an overproduction of acidic species in cancer cells. This acid overload must be counterbalanced with a high rate of H+ extrusion to maintain cell viability. In this sense, many H+ transporters have been reported to be crucial for cell survival and proposed as antineoplastic target. By the way, voltage-gated proton channels (Hv1) mediate highly selective H+ outward currents, capable to compensate acid burden in brief periods of time. This structure is canonically described acting as NADPH oxidase counterbalance in reactive oxygen species production. In this work, we show, for the first time in a oncohematologic cell line, that inhibition of Hv1 channels by Zn2+ and the more selective blocker 2-(6-chloro-1H-benzimidazol-2-yl)guanidine (ClGBI) progressively decreases intracellular pH in resting conditions. This acidification is evident minutes after blockade and progresses under prolonged exposure (2, 17, and 48 h), and we firstly demonstrate that this is followed by cell death through apoptosis (annexin V binding). Altogether, these results contribute strong evidence that this channel might be a new therapeutic target in cancer.

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Acknowledgements

The authors wish to thank Mr. Angel Flores, Ms. Julia De Santis, and Mr. Leandro Diaz Zegarra for their technical assistance. This study was financially supported by grant 11X652 Universidad Nacional de La Plata to Verónica Milesi, Fondecyt grant 1160261 to Carlos González León, PICT 2014-0603 to Pedro Martín, and PICT 2012-1772 to Guillermo Docena from the Agencia Nacional de Promoción Científica y Tecnológica (ANPCYT).

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  1. Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP, CONICET—Universidad Nacional de la Plata), Fac. de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115, 1900, La Plata, Argentina

    Agustín Asuaje, Paola Smaldini, Pedro Martín, Nicolás Enrique, Guillermo Docena & Verónica Milesi

  2. Centro de Investigaciones Cardiovasculares (CIC, CONICET—Universidad Nacional de la Plata), Fac. de Ciencias Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina

    Alejandro Orlowski & Ernesto A. Aiello

  3. Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Chile, Pasaje Harrington 287, Playa Ancha, Valparaíso, Chile

    Carlos Gonzalez León

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  1. Agustín Asuaje
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  2. Paola Smaldini
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Asuaje, A., Smaldini, P., Martín, P. et al. The inhibition of voltage-gated H+ channel (HVCN1) induces acidification of leukemic Jurkat T cells promoting cell death by apoptosis. Pflugers Arch - Eur J Physiol 469, 251–261 (2017). https://doi.org/10.1007/s00424-016-1928-0

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