STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1
Abstract 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 im...
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doaj-60246eddb1414b4e84c66433b39df47f2020-11-25T01:54:26ZengBMCCell & Bioscience2045-37012019-01-019111410.1186/s13578-018-0265-8STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1María Elisa Picco0María Victoria Castro1María Josefina Quezada2Gastón Barbero3María Belén Villanueva4Natalia Brenda Fernández5Hyungsoo Kim6Pablo Lopez-Bergami7Instituto de Medicina y Biología Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico (CEBBAD), Universidad Maimónides, CONICETCentro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico (CEBBAD), Universidad Maimónides, CONICETCentro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico (CEBBAD), Universidad Maimónides, CONICETCentro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico (CEBBAD), Universidad Maimónides, CONICETInstituto de Medicina y Biología Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)Sanford Burnham Prebys Medical Discovery InstituteCentro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico (CEBBAD), Universidad Maimónides, CONICETAbstract 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 characterized. 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 transcription through two STAT3 responsive elements. Transduction of WM9 and UACC903 melanoma cells with STAT3-small 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 effect of STAT3 silencing on Akt phosphorylation was restored by HA-PDK1. Along this line, HA-PDK1 expression significantly blocked the cell death induced by dacarbazine plus STAT3 knockdown. This effect 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 effort to therapeutically target STAT3 and PDK1 in melanoma and, possibly, other malignancies.http://link.springer.com/article/10.1186/s13578-018-0265-8STAT3PDK1AktPKCSGKMelanoma |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
María Elisa Picco María Victoria Castro María Josefina Quezada Gastón Barbero María Belén Villanueva Natalia Brenda Fernández Hyungsoo Kim Pablo Lopez-Bergami |
spellingShingle |
María Elisa Picco María Victoria Castro María Josefina Quezada Gastón Barbero María Belén Villanueva Natalia Brenda Fernández Hyungsoo Kim Pablo Lopez-Bergami STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1 Cell & Bioscience STAT3 PDK1 Akt PKC SGK Melanoma |
author_facet |
María Elisa Picco María Victoria Castro María Josefina Quezada Gastón Barbero María Belén Villanueva Natalia Brenda Fernández Hyungsoo Kim Pablo Lopez-Bergami |
author_sort |
María Elisa Picco |
title |
STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1 |
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 |
publisher |
BMC |
series |
Cell & Bioscience |
issn |
2045-3701 |
publishDate |
2019-01-01 |
description |
Abstract 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 characterized. 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 transcription through two STAT3 responsive elements. Transduction of WM9 and UACC903 melanoma cells with STAT3-small 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 effect of STAT3 silencing on Akt phosphorylation was restored by HA-PDK1. Along this line, HA-PDK1 expression significantly blocked the cell death induced by dacarbazine plus STAT3 knockdown. This effect 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 effort to therapeutically target STAT3 and PDK1 in melanoma and, possibly, other malignancies. |
topic |
STAT3 PDK1 Akt PKC SGK Melanoma |
url |
http://link.springer.com/article/10.1186/s13578-018-0265-8 |
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