STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1

Autores
Picco, María Elisa; Castro, María Victoria; Quezada, Maria Josefina; Barbero, Gastón Alexis; Villanueva, María Belén; Fernández, Natalia Brenda; Kim, Hyungsoo; Lopez Bergami, Pablo Roberto
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: The PI3K/Akt and the STAT3 pathways are functionally associated in many tumor types. Both in vitro and in vivo studies have revealed that either biochemical or genetic manipulation of the STAT3 pathway activity induce changes in the same direction in Akt activity. However, the implicated mechanism has been poorly character‑ ized. Our goal was to characterize the precise mechanism linking STAT3 with the activity of Akt and other AGC kinases in cancer using melanoma cells as a model. Results: We show that active STAT3 is constitutively bound to the PDK1 promoter and positively regulate PDK1 tran‑ scription through two STAT3 responsive elements. Transduction of WM9 and UACC903 melanoma cells with STAT3small hairpin RNA decreased both PDK1 mRNA and protein levels. STAT3 knockdown also induced a decrease of the phosphorylation of AGC kinases Akt, PKC, and SGK. The inhibitory efect of STAT3 silencing on Akt phosphorylation was restored by HA-PDK1. Along this line, HA-PDK1 expression signifcantly blocked the cell death induced by dac‑ arbazine plus STAT3 knockdown. This efect might be mediated by Bcl2 proteins since HA-PDK1 rescued Bcl2, Bcl-XL, and Mcl1 levels that were down-regulated upon STAT3 silencing. Conclusions: We show that PDK1 is a transcriptional target of STAT3, linking STAT3 pathway with AGC kinases activity in melanoma. These data provide further rationale for the ongoing efort to therapeutically target STAT3 and PDK1 in melanoma and, possibly, other malignancies.
Fil: Picco, María Elisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Castro, María Victoria. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Quezada, Maria Josefina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Barbero, Gastón Alexis. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Villanueva, María Belén. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fernández, Natalia Brenda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Kim, Hyungsoo. Sanford-burnham Medical Research Institute; Estados Unidos
Fil: Lopez Bergami, Pablo Roberto. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
AKT
MELANOMA
PDK1
PKC
SGK
STAT3
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/117520
Acceder
id CONICETDig_69c2c6c242efc45b6707a18ceaed04c5
oai_identifier_str oai:ri.conicet.gov.ar:11336/117520
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1Picco, María ElisaCastro, María VictoriaQuezada, Maria JosefinaBarbero, Gastón AlexisVillanueva, María BelénFernández, Natalia BrendaKim, HyungsooLopez Bergami, Pablo RobertoAKTMELANOMAPDK1PKCSGKSTAT3https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background: The PI3K/Akt and the STAT3 pathways are functionally associated in many tumor types. Both in vitro and in vivo studies have revealed that either biochemical or genetic manipulation of the STAT3 pathway activity induce changes in the same direction in Akt activity. However, the implicated mechanism has been poorly character‑ ized. Our goal was to characterize the precise mechanism linking STAT3 with the activity of Akt and other AGC kinases in cancer using melanoma cells as a model. Results: We show that active STAT3 is constitutively bound to the PDK1 promoter and positively regulate PDK1 tran‑ scription through two STAT3 responsive elements. Transduction of WM9 and UACC903 melanoma cells with STAT3small hairpin RNA decreased both PDK1 mRNA and protein levels. STAT3 knockdown also induced a decrease of the phosphorylation of AGC kinases Akt, PKC, and SGK. The inhibitory efect of STAT3 silencing on Akt phosphorylation was restored by HA-PDK1. Along this line, HA-PDK1 expression signifcantly blocked the cell death induced by dac‑ arbazine plus STAT3 knockdown. This efect might be mediated by Bcl2 proteins since HA-PDK1 rescued Bcl2, Bcl-XL, and Mcl1 levels that were down-regulated upon STAT3 silencing. Conclusions: We show that PDK1 is a transcriptional target of STAT3, linking STAT3 pathway with AGC kinases activity in melanoma. These data provide further rationale for the ongoing efort to therapeutically target STAT3 and PDK1 in melanoma and, possibly, other malignancies.Fil: Picco, María Elisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Castro, María Victoria. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Quezada, Maria Josefina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barbero, Gastón Alexis. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Villanueva, María Belén. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fernández, Natalia Brenda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Kim, Hyungsoo. Sanford-burnham Medical Research Institute; Estados UnidosFil: Lopez Bergami, Pablo Roberto. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaBioMed Central2019-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/117520Picco, María Elisa; Castro, María Victoria; Quezada, Maria Josefina; Barbero, Gastón Alexis; Villanueva, María Belén; et al.; STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1; BioMed Central; Cell and Bioscience; 9; 3; 1-2019; 1-142045-3701CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-018-0265-8info:eu-repo/semantics/altIdentifier/doi/10.1186/s13578-018-0265-8info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:48:15Zoai:ri.conicet.gov.ar:11336/117520instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:48:15.674CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1
title STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1
spellingShingle STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1
Picco, María Elisa
AKT
MELANOMA
PDK1
PKC
SGK
STAT3
title_short STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1
title_full STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1
title_fullStr STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1
title_full_unstemmed STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1
title_sort STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1
dc.creator.none.fl_str_mv Picco, María Elisa
Castro, María Victoria
Quezada, Maria Josefina
Barbero, Gastón Alexis
Villanueva, María Belén
Fernández, Natalia Brenda
Kim, Hyungsoo
Lopez Bergami, Pablo Roberto
author Picco, María Elisa
author_facet Picco, María Elisa
Castro, María Victoria
Quezada, Maria Josefina
Barbero, Gastón Alexis
Villanueva, María Belén
Fernández, Natalia Brenda
Kim, Hyungsoo
Lopez Bergami, Pablo Roberto
author_role author
author2 Castro, María Victoria
Quezada, Maria Josefina
Barbero, Gastón Alexis
Villanueva, María Belén
Fernández, Natalia Brenda
Kim, Hyungsoo
Lopez Bergami, Pablo Roberto
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv AKT
MELANOMA
PDK1
PKC
SGK
STAT3
topic AKT
MELANOMA
PDK1
PKC
SGK
STAT3
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background: The PI3K/Akt and the STAT3 pathways are functionally associated in many tumor types. Both in vitro and in vivo studies have revealed that either biochemical or genetic manipulation of the STAT3 pathway activity induce changes in the same direction in Akt activity. However, the implicated mechanism has been poorly character‑ ized. Our goal was to characterize the precise mechanism linking STAT3 with the activity of Akt and other AGC kinases in cancer using melanoma cells as a model. Results: We show that active STAT3 is constitutively bound to the PDK1 promoter and positively regulate PDK1 tran‑ scription through two STAT3 responsive elements. Transduction of WM9 and UACC903 melanoma cells with STAT3small hairpin RNA decreased both PDK1 mRNA and protein levels. STAT3 knockdown also induced a decrease of the phosphorylation of AGC kinases Akt, PKC, and SGK. The inhibitory efect of STAT3 silencing on Akt phosphorylation was restored by HA-PDK1. Along this line, HA-PDK1 expression signifcantly blocked the cell death induced by dac‑ arbazine plus STAT3 knockdown. This efect might be mediated by Bcl2 proteins since HA-PDK1 rescued Bcl2, Bcl-XL, and Mcl1 levels that were down-regulated upon STAT3 silencing. Conclusions: We show that PDK1 is a transcriptional target of STAT3, linking STAT3 pathway with AGC kinases activity in melanoma. These data provide further rationale for the ongoing efort to therapeutically target STAT3 and PDK1 in melanoma and, possibly, other malignancies.
Fil: Picco, María Elisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Castro, María Victoria. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Quezada, Maria Josefina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Barbero, Gastón Alexis. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Villanueva, María Belén. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fernández, Natalia Brenda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Kim, Hyungsoo. Sanford-burnham Medical Research Institute; Estados Unidos
Fil: Lopez Bergami, Pablo Roberto. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Background: The PI3K/Akt and the STAT3 pathways are functionally associated in many tumor types. Both in vitro and in vivo studies have revealed that either biochemical or genetic manipulation of the STAT3 pathway activity induce changes in the same direction in Akt activity. However, the implicated mechanism has been poorly character‑ ized. Our goal was to characterize the precise mechanism linking STAT3 with the activity of Akt and other AGC kinases in cancer using melanoma cells as a model. Results: We show that active STAT3 is constitutively bound to the PDK1 promoter and positively regulate PDK1 tran‑ scription through two STAT3 responsive elements. Transduction of WM9 and UACC903 melanoma cells with STAT3small hairpin RNA decreased both PDK1 mRNA and protein levels. STAT3 knockdown also induced a decrease of the phosphorylation of AGC kinases Akt, PKC, and SGK. The inhibitory efect of STAT3 silencing on Akt phosphorylation was restored by HA-PDK1. Along this line, HA-PDK1 expression signifcantly blocked the cell death induced by dac‑ arbazine plus STAT3 knockdown. This efect might be mediated by Bcl2 proteins since HA-PDK1 rescued Bcl2, Bcl-XL, and Mcl1 levels that were down-regulated upon STAT3 silencing. Conclusions: We show that PDK1 is a transcriptional target of STAT3, linking STAT3 pathway with AGC kinases activity in melanoma. These data provide further rationale for the ongoing efort to therapeutically target STAT3 and PDK1 in melanoma and, possibly, other malignancies.
publishDate 2019
dc.date.none.fl_str_mv 2019-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/117520
Picco, María Elisa; Castro, María Victoria; Quezada, Maria Josefina; Barbero, Gastón Alexis; Villanueva, María Belén; et al.; STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1; BioMed Central; Cell and Bioscience; 9; 3; 1-2019; 1-14
2045-3701
CONICET Digital
CONICET
url http://hdl.handle.net/11336/117520
identifier_str_mv Picco, María Elisa; Castro, María Victoria; Quezada, Maria Josefina; Barbero, Gastón Alexis; Villanueva, María Belén; et al.; STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1; BioMed Central; Cell and Bioscience; 9; 3; 1-2019; 1-14
2045-3701
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-018-0265-8
info:eu-repo/semantics/altIdentifier/doi/10.1186/s13578-018-0265-8
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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