Cross-talk entre las vías de Wnt5a y NF-kB en melanoma
Wnt5a is over-expressed in melanoma and contributes to the motility, invasion and metastasis of these cells. Our results indicate that Wnt5a activates the NF-kB pathway, promoting p65 phosphorylation and nuclear translocation, IKK complex phosphorylation and IkBa degradation. This process is depende...
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Formato: | Tesis doctoral acceptedVersion |
Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2019
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Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_2964 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_2964.dir/2964.PDF |
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I28-R145-HWA_29642020-07-05 Wnt5a is over-expressed in melanoma and contributes to the motility, invasion and metastasis of these cells. Our results indicate that Wnt5a activates the NF-kB pathway, promoting p65 phosphorylation and nuclear translocation, IKK complex phosphorylation and IkBa degradation. This process is dependent on ROR1 and Dvl2, members of the Wnt pathway, as well as on TRAF2 and NIK, members of the NF-kB pathway. This response requires Akt and its inhibition prevents the activation of p65. However, in the SK-Mel28 cell line Akt is dispensable and the response is mediated by PKCo and GSK3b. We also showed that through an autocrine loop Wnt5a regulates the expression and basal activity of NF-kB. Finally, Wnt5a increases NF-kB transcriptional activity and promotes the release of pro-inflammatory cytokines. In sum, we demonstrated a new role for Wnt5a in cancer that thanks to the activation of NF-kB, promotes the synthesis of inflammatory cytokines, contributing to create the inflammatory and immunosupressive conditions that would allow melanoma cells to evade the immune response in the tumor microenvironment. These findings strength the role of Wnt5a as a new and promissory therapeutic target in melanoma. Fil: Barbero, Gastón Alexis. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Buenos Aires, Argentina Roguin, Leonor Facultad de Farmacia y Bioquímica Lopez-Bergami, Pablo Barbero, Gastón Alexis 2019-03-20 El ligando Wnt5a se encuentra sobre-expresado en melanoma y posee un rol en la motilidad, invasión y metástasis de estas células. Nuestros resultados indican que Wnt5a activa la vía de NF-kB, promoviendo la fosforilación y traslocación nuclear de p65, la fosforilación del complejo IKK y la degradación de IkBa. Este proceso es dependiente de ROR1 y Dvl2, miembros de la vía Wnt, y de TRAF2 y NIK, componentes de la vía NF-kB. Esta respuesta requiere de Akt y su inhibición impide la activación de p65. No obstante, en la línea SK-Mel 28, Akt es dispensable y la respuesta es mediada por PKCo y GSK3b. También demostramos que mediante un circuito autócrino Wnt5a regula la expresión y actividad basal de NF-kB. Finalmente, Wnt5a aumenta la actividad transcripcional de NF-kB y promueve la liberación de citoquinas pro-inflamatorias. En suma, demostramos un nuevo rol de Wnt5a en cáncer, que gracias a la activación de NF-kB, promueve la síntesis de citoquinas inflamatorias y contribuiría a crear el entorno inflamatorio e inmunosupresor que permite a las células de melanoma evadir la respuesta inmune del paciente en el microambiente tumoral. Estos resultados refuerzan la caracterización de Wnt5a como un nuevo y promisorio blanco terapéutico en melanoma. application/pdf González, Lorena Eijan, Ana María Irusta, Griselda Melanoma Wnt5a NF-kB Citoquinas Cross-talk Melanoma Wnt5a NF-kB Cytokines Cross-talk spa Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ Ciencias de la vida Cross-talk entre las vías de Wnt5a y NF-kB en melanoma info:eu-repo/semantics/doctoralThesis info:ar-repo/semantics/tesis doctoral info:eu-repo/semantics/acceptedVersion http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_2964 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_2964.dir/2964.PDF |
institution |
Universidad de Buenos Aires |
institution_str |
I-28 |
repository_str |
R-145 |
collection |
Repositorio Digital de la Universidad de Buenos Aires (UBA) |
language |
Español |
orig_language_str_mv |
spa |
topic |
Melanoma Wnt5a NF-kB Citoquinas Cross-talk Melanoma Wnt5a NF-kB Cytokines Cross-talk Ciencias de la vida |
spellingShingle |
Melanoma Wnt5a NF-kB Citoquinas Cross-talk Melanoma Wnt5a NF-kB Cytokines Cross-talk Ciencias de la vida Barbero, Gastón Alexis Cross-talk entre las vías de Wnt5a y NF-kB en melanoma |
topic_facet |
Melanoma Wnt5a NF-kB Citoquinas Cross-talk Melanoma Wnt5a NF-kB Cytokines Cross-talk Ciencias de la vida |
description |
Wnt5a is over-expressed in melanoma and contributes to the motility, invasion and metastasis of these cells. Our results indicate that Wnt5a activates the NF-kB pathway, promoting p65 phosphorylation and nuclear translocation, IKK complex phosphorylation and IkBa degradation. This process is dependent on ROR1 and Dvl2, members of the Wnt pathway, as well as on TRAF2 and NIK, members of the NF-kB pathway. This response requires Akt and its inhibition prevents the activation of p65. However, in the SK-Mel28 cell line Akt is dispensable and the response is mediated by PKCo and GSK3b. We also showed that through an autocrine loop Wnt5a regulates the expression and basal activity of NF-kB. Finally, Wnt5a increases NF-kB transcriptional activity and promotes the release of pro-inflammatory cytokines. In sum, we demonstrated a new role for Wnt5a in cancer that thanks to the activation of NF-kB, promotes the synthesis of inflammatory cytokines, contributing to create the inflammatory and immunosupressive conditions that would allow melanoma cells to evade the immune response in the tumor microenvironment. These findings strength the role of Wnt5a as a new and promissory therapeutic target in melanoma. |
author2 |
Roguin, Leonor |
author_facet |
Roguin, Leonor Barbero, Gastón Alexis |
format |
Tesis doctoral Tesis doctoral acceptedVersion |
author |
Barbero, Gastón Alexis |
author_sort |
Barbero, Gastón Alexis |
title |
Cross-talk entre las vías de Wnt5a y NF-kB en melanoma |
title_short |
Cross-talk entre las vías de Wnt5a y NF-kB en melanoma |
title_full |
Cross-talk entre las vías de Wnt5a y NF-kB en melanoma |
title_fullStr |
Cross-talk entre las vías de Wnt5a y NF-kB en melanoma |
title_full_unstemmed |
Cross-talk entre las vías de Wnt5a y NF-kB en melanoma |
title_sort |
cross-talk entre las vías de wnt5a y nf-kb en melanoma |
publisher |
Facultad de Farmacia y Bioquímica |
publishDate |
2019 |
url |
http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_2964 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_2964.dir/2964.PDF |
work_keys_str_mv |
AT barberogastonalexis crosstalkentrelasviasdewnt5aynfkbenmelanoma |
_version_ |
1766017523454574592 |