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PI3K-AKT-mTOR Pathway is Dominant over Androgen Receptor Signaling in Prostate Cancer Cells

Background: Androgen receptor (AR) and the phosphatidylinositol-3 kinase (PI3K) signaling are two of the most important pathways implicated in prostate cancer. Previous work has shown that there is crosstalk between these two pathways; however, there are conflicting findings and the molecular mechan...

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Autores principales: Kaarbø, Mari, Mikkelsen, Øyvind Løveseter, Malerød, Lene, Qu, Su, Lobert, Viola H., Akgul, Gulcan, Halvorsen, Thomas, Mælandsmo, Gunhild M., Saatcioglu, Fahri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: IOS Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619056/
https://www.ncbi.nlm.nih.gov/pubmed/20203370
http://dx.doi.org/10.3233/CLO-2009-0487
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author Kaarbø, Mari
Mikkelsen, Øyvind Løveseter
Malerød, Lene
Qu, Su
Lobert, Viola H.
Akgul, Gulcan
Halvorsen, Thomas
Mælandsmo, Gunhild M.
Saatcioglu, Fahri
author_facet Kaarbø, Mari
Mikkelsen, Øyvind Løveseter
Malerød, Lene
Qu, Su
Lobert, Viola H.
Akgul, Gulcan
Halvorsen, Thomas
Mælandsmo, Gunhild M.
Saatcioglu, Fahri
author_sort Kaarbø, Mari
collection PubMed
description Background: Androgen receptor (AR) and the phosphatidylinositol-3 kinase (PI3K) signaling are two of the most important pathways implicated in prostate cancer. Previous work has shown that there is crosstalk between these two pathways; however, there are conflicting findings and the molecular mechanisms are not clear. Here we studied the AR–PI3K pathway crosstalk in prostate cancer cells in vitro as well as in vivo. Methods: Quantitative PCR, Western analysis, reporter assays, and proliferation analyses in vitro and in vivo were used to evaluate the effect of PI3K pathway inhibition on AR signaling and cell growth. Results: Transcriptional activity of AR was increased when the PI3K pathway was inhibited at different levels. In the androgen responsive prostate cancer cell line LNCaP, androgen and the mTOR inhibitor rapamycin synergistically activated androgen target genes. Despite increased androgen signaling, rapamycin treatment reduced LNCaP cell growth; the AR antagonist bicalutamide potentiated this effect. Furthermore, the rapamycin derivative CCI-779 reduced the growth of CWR22 prostate cancer xenografts while increasing AR target gene expression. Conclusions: These findings suggest that inhibition of the PI3K pathway activates AR signaling. Despite the increase in AR signaling which has proliferative effects, the result of PI3K pathway inhibition is antiproliferative. These findings suggest that the PI3K pathway is dominant over AR signaling in prostate cancer cells which should be considered in developing novel therapeutic strategies for prostate cancer.
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spelling pubmed-46190562016-01-12 PI3K-AKT-mTOR Pathway is Dominant over Androgen Receptor Signaling in Prostate Cancer Cells Kaarbø, Mari Mikkelsen, Øyvind Løveseter Malerød, Lene Qu, Su Lobert, Viola H. Akgul, Gulcan Halvorsen, Thomas Mælandsmo, Gunhild M. Saatcioglu, Fahri Cell Oncol Other Background: Androgen receptor (AR) and the phosphatidylinositol-3 kinase (PI3K) signaling are two of the most important pathways implicated in prostate cancer. Previous work has shown that there is crosstalk between these two pathways; however, there are conflicting findings and the molecular mechanisms are not clear. Here we studied the AR–PI3K pathway crosstalk in prostate cancer cells in vitro as well as in vivo. Methods: Quantitative PCR, Western analysis, reporter assays, and proliferation analyses in vitro and in vivo were used to evaluate the effect of PI3K pathway inhibition on AR signaling and cell growth. Results: Transcriptional activity of AR was increased when the PI3K pathway was inhibited at different levels. In the androgen responsive prostate cancer cell line LNCaP, androgen and the mTOR inhibitor rapamycin synergistically activated androgen target genes. Despite increased androgen signaling, rapamycin treatment reduced LNCaP cell growth; the AR antagonist bicalutamide potentiated this effect. Furthermore, the rapamycin derivative CCI-779 reduced the growth of CWR22 prostate cancer xenografts while increasing AR target gene expression. Conclusions: These findings suggest that inhibition of the PI3K pathway activates AR signaling. Despite the increase in AR signaling which has proliferative effects, the result of PI3K pathway inhibition is antiproliferative. These findings suggest that the PI3K pathway is dominant over AR signaling in prostate cancer cells which should be considered in developing novel therapeutic strategies for prostate cancer. IOS Press 2010 2010-02-04 /pmc/articles/PMC4619056/ /pubmed/20203370 http://dx.doi.org/10.3233/CLO-2009-0487 Text en Copyright © 2010 Hindawi Publishing Corporation and the authors.
spellingShingle Other
Kaarbø, Mari
Mikkelsen, Øyvind Løveseter
Malerød, Lene
Qu, Su
Lobert, Viola H.
Akgul, Gulcan
Halvorsen, Thomas
Mælandsmo, Gunhild M.
Saatcioglu, Fahri
PI3K-AKT-mTOR Pathway is Dominant over Androgen Receptor Signaling in Prostate Cancer Cells
title PI3K-AKT-mTOR Pathway is Dominant over Androgen Receptor Signaling in Prostate Cancer Cells
title_full PI3K-AKT-mTOR Pathway is Dominant over Androgen Receptor Signaling in Prostate Cancer Cells
title_fullStr PI3K-AKT-mTOR Pathway is Dominant over Androgen Receptor Signaling in Prostate Cancer Cells
title_full_unstemmed PI3K-AKT-mTOR Pathway is Dominant over Androgen Receptor Signaling in Prostate Cancer Cells
title_short PI3K-AKT-mTOR Pathway is Dominant over Androgen Receptor Signaling in Prostate Cancer Cells
title_sort pi3k-akt-mtor pathway is dominant over androgen receptor signaling in prostate cancer cells
topic Other
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619056/
https://www.ncbi.nlm.nih.gov/pubmed/20203370
http://dx.doi.org/10.3233/CLO-2009-0487
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