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Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten−/− melanoma
Phosphoinositide-dependent kinase-1 (PDK-1) is a serine/threonine protein kinase that phosphorylates members of the conserved AGC kinase superfamily, including AKT and PKC, and is implicated in important cellular processes including survival, metabolism and tumorigenesis. In large cohorts of nevi an...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2013
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955742/ https://www.ncbi.nlm.nih.gov/pubmed/24037523 http://dx.doi.org/10.1038/onc.2013.383 |
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author | Scortegagna, Marzia Ruller, Chelsea Feng, Yongmei Lazova, Rossitza Kluger, Harriet Li, Jian-Liang De, Surya K Rickert, Robert Pellecchia, Maurizio Bosenberg, Marcus Ronai, Ze’ev A. |
author_facet | Scortegagna, Marzia Ruller, Chelsea Feng, Yongmei Lazova, Rossitza Kluger, Harriet Li, Jian-Liang De, Surya K Rickert, Robert Pellecchia, Maurizio Bosenberg, Marcus Ronai, Ze’ev A. |
author_sort | Scortegagna, Marzia |
collection | PubMed |
description | Phosphoinositide-dependent kinase-1 (PDK-1) is a serine/threonine protein kinase that phosphorylates members of the conserved AGC kinase superfamily, including AKT and PKC, and is implicated in important cellular processes including survival, metabolism and tumorigenesis. In large cohorts of nevi and melanoma samples, PDK1 expression was significantly higher in primary melanoma, compared with nevi, and was further increased in metastatic melanoma. PDK1 expression suffices for its activity, due to auto-activation, or elevated phosphorylation by phosphoinositide 3'-OH-kinase (PI 3-K). Selective inactivation of Pdk1 in the melanocytes of Braf(V600E)::Pten(−/−) or Braf(V600E)::Cdkn2a(−/−)::Pten(−/−) mice delayed the development of pigmented lesions and melanoma induced by systemic or local administration of 4-HT. Melanoma invasion and metastasis were significantly reduced or completely prevented by Pdk1 deletion. Administration of the PDK1 inhibitor GSK2334470 (PDKi) effectively delayed melanomagenesis and metastasis in Braf(V600E)::Pten(−/−) mice. Pdk1(−/−) melanomas exhibit a marked decrease in the activity of AKT, P70S6K and PKC. Notably, PDKi was as effective in inhibiting AGC kinases and colony forming efficiency of melanoma with Pten WT genotypes. Gene expression analyses identified Pdk1-dependent changes in FOXO3a-regulated genes and inhibition of FOXO3a restored proliferation and colony formation of Pdk1(−/−) melanoma cells. Our studies provide direct genetic evidence for the importance of PDK1, in part through FOXO3a-dependent pathway, in melanoma development and progression. |
format | Online Article Text |
id | pubmed-3955742 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
record_format | MEDLINE/PubMed |
spelling | pubmed-39557422015-02-21 Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten−/− melanoma Scortegagna, Marzia Ruller, Chelsea Feng, Yongmei Lazova, Rossitza Kluger, Harriet Li, Jian-Liang De, Surya K Rickert, Robert Pellecchia, Maurizio Bosenberg, Marcus Ronai, Ze’ev A. Oncogene Article Phosphoinositide-dependent kinase-1 (PDK-1) is a serine/threonine protein kinase that phosphorylates members of the conserved AGC kinase superfamily, including AKT and PKC, and is implicated in important cellular processes including survival, metabolism and tumorigenesis. In large cohorts of nevi and melanoma samples, PDK1 expression was significantly higher in primary melanoma, compared with nevi, and was further increased in metastatic melanoma. PDK1 expression suffices for its activity, due to auto-activation, or elevated phosphorylation by phosphoinositide 3'-OH-kinase (PI 3-K). Selective inactivation of Pdk1 in the melanocytes of Braf(V600E)::Pten(−/−) or Braf(V600E)::Cdkn2a(−/−)::Pten(−/−) mice delayed the development of pigmented lesions and melanoma induced by systemic or local administration of 4-HT. Melanoma invasion and metastasis were significantly reduced or completely prevented by Pdk1 deletion. Administration of the PDK1 inhibitor GSK2334470 (PDKi) effectively delayed melanomagenesis and metastasis in Braf(V600E)::Pten(−/−) mice. Pdk1(−/−) melanomas exhibit a marked decrease in the activity of AKT, P70S6K and PKC. Notably, PDKi was as effective in inhibiting AGC kinases and colony forming efficiency of melanoma with Pten WT genotypes. Gene expression analyses identified Pdk1-dependent changes in FOXO3a-regulated genes and inhibition of FOXO3a restored proliferation and colony formation of Pdk1(−/−) melanoma cells. Our studies provide direct genetic evidence for the importance of PDK1, in part through FOXO3a-dependent pathway, in melanoma development and progression. 2013-09-16 2014-08-21 /pmc/articles/PMC3955742/ /pubmed/24037523 http://dx.doi.org/10.1038/onc.2013.383 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Scortegagna, Marzia Ruller, Chelsea Feng, Yongmei Lazova, Rossitza Kluger, Harriet Li, Jian-Liang De, Surya K Rickert, Robert Pellecchia, Maurizio Bosenberg, Marcus Ronai, Ze’ev A. Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten−/− melanoma |
title | Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten−/− melanoma |
title_full | Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten−/− melanoma |
title_fullStr | Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten−/− melanoma |
title_full_unstemmed | Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten−/− melanoma |
title_short | Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten−/− melanoma |
title_sort | genetic inactivation or pharmacological inhibition of pdk1 delays development and inhibits metastasis of braf(v600e)::pten−/− melanoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955742/ https://www.ncbi.nlm.nih.gov/pubmed/24037523 http://dx.doi.org/10.1038/onc.2013.383 |
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