title: The inhibition of voltage-gated H+channel (HVCN1) induces acidification of leukemic Jurkat T cells promoting cell death by apoptosis.
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.
authors.affiliation: 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.
authors.forename: Agustín
authors.initials: A
authors.lastname: Asuaje
authors.affiliation: 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.
authors.forename: Paola
authors.initials: P
authors.lastname: Smaldini
authors.affiliation: 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. pedromartinv@gmail.com.
authors.forename: Pedro
authors.initials: P
authors.lastname: Martín
authors.affiliation: 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.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Enrique
authors.affiliation: 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.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Orlowski
authors.affiliation: 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.
authors.forename: Ernesto A
authors.initials: EA
authors.lastname: Aiello
authors.affiliation: Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Chile, Pasaje Harrington 287, Playa Ancha, Valparaíso, Chile.
authors.forename: Carlos
authors.initials: C
authors.lastname: Gonzalez León
authors.affiliation: 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.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Docena
authors.affiliation: 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.
authors.forename: Verónica
authors.initials: V
authors.lastname: Milesi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019169:Jurkat Cells; D019255:NADPH Oxidases / Q000378:metabolism; D011522:Protons; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C510235:HVCN1 protein, human; D007473:Ion Channels; D011522:Protons; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D015032:Zinc
keywords: Apoptosis; Cancer; HVCN1; Intracellular pH; Leukemia; Voltage-gated proton channel