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Cellular Oncology
Volume 32 (2010), Issue 1-2, Pages 11-27
http://dx.doi.org/10.3233/CLO-2009-0487

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

Mari Kaarbø,1 Øyvind Løveseter Mikkelsen,1 Lene Malerød,1 Su Qu,1 Viola H. Lobert,1 Gulcan Akgul,1 Thomas Halvorsen,2 Gunhild M. Mælandsmo,2 and Fahri Saatcioglu1

1Department of Molecular Biosciences, University of Oslo, Oslo, Norway
2Department of Tumor Biology, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway

Copyright © 2010 Hindawi Publishing Corporation and the authors. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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.