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Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells

The phosphatidylinositol 3-kinase (PI3K)-Akt-mechanistic target of rapamycin (mTOR) pathway is constitutively activated in human acute myeloid leukemia (AML) cells and is regarded as a possible therapeutic target. Insulin is an agonist of this pathway and a growth factor for AML cells. We characteri...

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Autores principales: Nepstad, Ina, Hatfield, Kimberley Joanne, Grønningsæter, Ida Sofie, Aasebø, Elise, Hernandez-Valladares, Maria, Hagen, Karen Marie, Rye, Kristin Paulsen, Berven, Frode S., Selheim, Frode, Reikvam, Håkon, Bruserud, Øystein
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582141/
https://www.ncbi.nlm.nih.gov/pubmed/31240133
http://dx.doi.org/10.1038/s41392-019-0050-0
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author Nepstad, Ina
Hatfield, Kimberley Joanne
Grønningsæter, Ida Sofie
Aasebø, Elise
Hernandez-Valladares, Maria
Hagen, Karen Marie
Rye, Kristin Paulsen
Berven, Frode S.
Selheim, Frode
Reikvam, Håkon
Bruserud, Øystein
author_facet Nepstad, Ina
Hatfield, Kimberley Joanne
Grønningsæter, Ida Sofie
Aasebø, Elise
Hernandez-Valladares, Maria
Hagen, Karen Marie
Rye, Kristin Paulsen
Berven, Frode S.
Selheim, Frode
Reikvam, Håkon
Bruserud, Øystein
author_sort Nepstad, Ina
collection PubMed
description The phosphatidylinositol 3-kinase (PI3K)-Akt-mechanistic target of rapamycin (mTOR) pathway is constitutively activated in human acute myeloid leukemia (AML) cells and is regarded as a possible therapeutic target. Insulin is an agonist of this pathway and a growth factor for AML cells. We characterized the effect of insulin on the phosphorylation of 10 mediators in the main track of the PI3K-Akt-mTOR pathway in AML cells from 76 consecutive patients. The overall results showed that insulin significantly increased the phosphorylation of all investigated mediators. However, insulin effects on the pathway activation profile varied among patients, and increased phosphorylation in all mediators was observed only in a minority of patients; in other patients, insulin had divergent effects. Global gene expression profiling and proteomic/phosphoproteomic comparisons suggested that AML cells from these two patient subsets differed with regard to AML cell differentiation, transcriptional regulation, RNA metabolism, and cellular metabolism. Strong insulin-induced phosphorylation was associated with weakened antiproliferative effects of metabolic inhibitors. PI3K, Akt, and mTOR inhibitors also caused divergent effects on the overall pathway phosphorylation profile in the presence of insulin, although PI3K and Akt inhibition caused a general reduction in Akt pT308 and 4EBP1 pT36/pT45 phosphorylation. For Akt inhibition, the phosphorylation of upstream mediators was generally increased or unaltered. In contrast, mTOR inhibition reduced mTOR pS2448 and S6 pS244 phosphorylation but increased Akt pT308 phosphorylation. In conclusion, the effects of both insulin and PI3K-Akt-mTOR inhibitors differ between AML patient subsets, and differences in insulin responsiveness are associated with differential susceptibility to metabolic targeting.
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spelling pubmed-65821412019-06-25 Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells Nepstad, Ina Hatfield, Kimberley Joanne Grønningsæter, Ida Sofie Aasebø, Elise Hernandez-Valladares, Maria Hagen, Karen Marie Rye, Kristin Paulsen Berven, Frode S. Selheim, Frode Reikvam, Håkon Bruserud, Øystein Signal Transduct Target Ther Article The phosphatidylinositol 3-kinase (PI3K)-Akt-mechanistic target of rapamycin (mTOR) pathway is constitutively activated in human acute myeloid leukemia (AML) cells and is regarded as a possible therapeutic target. Insulin is an agonist of this pathway and a growth factor for AML cells. We characterized the effect of insulin on the phosphorylation of 10 mediators in the main track of the PI3K-Akt-mTOR pathway in AML cells from 76 consecutive patients. The overall results showed that insulin significantly increased the phosphorylation of all investigated mediators. However, insulin effects on the pathway activation profile varied among patients, and increased phosphorylation in all mediators was observed only in a minority of patients; in other patients, insulin had divergent effects. Global gene expression profiling and proteomic/phosphoproteomic comparisons suggested that AML cells from these two patient subsets differed with regard to AML cell differentiation, transcriptional regulation, RNA metabolism, and cellular metabolism. Strong insulin-induced phosphorylation was associated with weakened antiproliferative effects of metabolic inhibitors. PI3K, Akt, and mTOR inhibitors also caused divergent effects on the overall pathway phosphorylation profile in the presence of insulin, although PI3K and Akt inhibition caused a general reduction in Akt pT308 and 4EBP1 pT36/pT45 phosphorylation. For Akt inhibition, the phosphorylation of upstream mediators was generally increased or unaltered. In contrast, mTOR inhibition reduced mTOR pS2448 and S6 pS244 phosphorylation but increased Akt pT308 phosphorylation. In conclusion, the effects of both insulin and PI3K-Akt-mTOR inhibitors differ between AML patient subsets, and differences in insulin responsiveness are associated with differential susceptibility to metabolic targeting. Nature Publishing Group UK 2019-06-19 /pmc/articles/PMC6582141/ /pubmed/31240133 http://dx.doi.org/10.1038/s41392-019-0050-0 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Nepstad, Ina
Hatfield, Kimberley Joanne
Grønningsæter, Ida Sofie
Aasebø, Elise
Hernandez-Valladares, Maria
Hagen, Karen Marie
Rye, Kristin Paulsen
Berven, Frode S.
Selheim, Frode
Reikvam, Håkon
Bruserud, Øystein
Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells
title Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells
title_full Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells
title_fullStr Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells
title_full_unstemmed Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells
title_short Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells
title_sort effects of insulin and pathway inhibitors on the pi3k-akt-mtor phosphorylation profile in acute myeloid leukemia cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582141/
https://www.ncbi.nlm.nih.gov/pubmed/31240133
http://dx.doi.org/10.1038/s41392-019-0050-0
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