000065256 001__ 65256
000065256 005__ 20190709135631.0
000065256 0247_ $$2doi$$a10.1371/journal.pone.0190307
000065256 0248_ $$2sideral$$a104206
000065256 037__ $$aART-2018-104206
000065256 041__ $$aeng
000065256 100__ $$0(orcid)0000-0001-5348-924X$$aOlivan-Viguera, A.
000065256 245__ $$aPharmacological activation of TRPV4 produces immediate cell damage and induction of apoptosis in human melanoma cells and HaCaT keratinocytes
000065256 260__ $$c2018
000065256 5060_ $$aAccess copy available to the general public$$fUnrestricted
000065256 5203_ $$aBackground TRPV4 channels are calcium-permeable cation channels that are activated by several physicochemical stimuli. Accordingly, TRPV4 channels have been implicated in the regulation of osmosensing, mechanotransduction, thermosensation, and epithelial/endothelial barrier functions. Whether TRPV4 is also mechanistically implicated in melanoma cell proliferation is not clear. Here, we hypothesized that TRPV4 is expressed in human melanoma and that pharmacological activation interferes with cell proliferation. Methodology/Principal findings TRPV4 functions were studied in melanoma cell lines (A375, SK-MEL-28, MKTBR), immortalized non-cancer keratinocytes (HaCaT), and murine 3T3 fibroblasts by patch-clamp, qRT-PCR, intracellular calcium measurements, cell proliferation, and flow cytometric assays of apoptosis and cell cycle. The selective TRPV4-activator, GSK1016790A, elicited non-selective cation currents with TRPV4-typical current-voltage-relationship in all cell lines. GSK1016790A-induced currents were blocked by the TRPV4-blocker, HC067047. TRPV4 mRNA expression was demonstrated by qRT-PCR. In A375 cells, TRPV4 activation was frequently paralleled by co-activation of calcium/calmodulin-regulated KCa3.1 channels. Light microscopy showed that TRPV4-activation produced rapid cellular disarrangement, nuclear densification, and detachment of a large fraction of all melanoma cell lines and HaCaT cells. TRPV4-activation induced apoptosis and drastically inhibited A375 and HaCaT proliferation that could be partially prevented by HC067047. Conclusions/Significance Our study showed that TRPV4 channels were functionally expressed in human melanoma cell lines and in human keratinocytes. Pharmacological TRPV4 activation in human melanoma cells and keratinocytes caused severe cellular disarrangement, necrosis and apoptosis. Pharmacological targeting of TRPV4 could be an alternative or adjuvant therapeutic strategy to treat melanoma progression and other proliferative skin disorders.
000065256 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/DPI2016-75458-R$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 638284-MODELAGE$$9info:eu-repo/grantAgreement/EC/H2020/638284/EU/Is your heart aging well? A systems biology approach to characterize cardiac aging from the cell to the body surface/MODELAGE$$9info:eu-repo/grantAgreement/ES/DGA/T96$$9info:eu-repo/grantAgreement/ES/DGA/GIPASC-B105$$9info:eu-repo/grantAgreement/ES/MINECO/TIN2013-41998-R
000065256 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000065256 590__ $$a2.776$$b2018
000065256 591__ $$aMULTIDISCIPLINARY SCIENCES$$b23 / 69 = 0.333$$c2018$$dQ2$$eT2
000065256 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000065256 700__ $$0(orcid)0000-0002-5123-2480$$aGarcia-Otin, A.L.
000065256 700__ $$aLozano-Gerona, J.
000065256 700__ $$aAbarca-Lachen, E.
000065256 700__ $$aGarcia-Malinis, A.J.
000065256 700__ $$aHamilton, K.L.
000065256 700__ $$aGilaberte, Y.$$uUniversidad de Zaragoza
000065256 700__ $$0(orcid)0000-0002-1960-407X$$aPueyo, E.$$uUniversidad de Zaragoza
000065256 700__ $$aKöhler, R.
000065256 7102_ $$15008$$2800$$aUniversidad de Zaragoza$$bDpto. Ingeniería Electrón.Com.$$cÁrea Teoría Señal y Comunicac.
000065256 7102_ $$11007$$2183$$aUniversidad de Zaragoza$$bDpto. Medicina, Psiqu. y Derm.$$cArea Dermatología
000065256 773__ $$g13, 1 (2018), [19 pp]$$pPLoS One$$tPloS one$$x1932-6203
000065256 8564_ $$s20665778$$uhttp://zaguan.unizar.es/record/65256/files/texto_completo.pdf$$yVersión publicada
000065256 8564_ $$s104788$$uhttp://zaguan.unizar.es/record/65256/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000065256 909CO $$ooai:zaguan.unizar.es:65256$$particulos$$pdriver
000065256 951__ $$a2019-07-09-12:33:22
000065256 980__ $$aARTICLE