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Phosphoinositide 3-OH kinase p85α and p110β are essential for androgen receptor transactivation and tumor progression in prostate cancers

Oncogene volume 27, pages 4569–4579 (2008)Cite this article

Abstract

Phosphoinositide 3-OH kinases (PI3Ks) are a group of major intracellular signaling molecules. In our previous study, we found that inhibition of PI3K activity suppressed the androgen receptor (AR)-mediated gene expression in prostate cancer cells. The AR has been considered as a critical determinant for the development and progression of human prostate cancers. In this study, we sought to identify the PI3K isoforms involved in AR transactivation. Using a gene-specific small interference RNA (siRNA) approach, we determined that the regulatory isoform p85α and the catalytic isoform p110β, but not p110α, were required for androgen-stimulated AR transactivation and cell proliferation in prostate cancer cells. Consistently, overexpression of wild-type p110β but not p110α gene led to androgen-independent AR transactivation. Silencing p110β gene in prostate cancer cells abolished tumor growth in nude mice. Of the dual (lipid and protein) kinase activities, p110β’s lipid kinase activity was required for AR transactivation. Further analysis by a chromatin immunoprecipitation assay showed that p110β is indispensable for androgen-induced AR–DNA interaction. Finally, gene expression analysis of clinical specimens showed that both p85α and p110β were highly expressed in malignant prostate tissues compared to the nonmalignant compartments, and their expression levels correlated significantly with disease progression. Taken together, our data demonstrated that p85α and p110β are essential for androgen-stimulated AR transactivation, and their aberrant expression or activation might play an important role in prostate cancer progression.

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Abbreviations

AR:

androgen receptor

ARE:

androgen response element

BrdU:

Bromodeoxyuridine

ChIP:

chromatin IP

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PAGE:

polyacrylamide

PI3K:

phosphoinositide 3-OH kinase

PKO:

protein kinase only

PSA:

prostate-specific antigen

PTEN:

phosphatase and tensin homologue deleted on chromosome 10

RT:

reverse-transcription

SEAP:

secreted alkaline phosphatase

s.e.m.:

standard error of mean

siRNA:

small interference RNA

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Acknowledgements

We thank Dr Alen Gao at Roswell Park Cancer Institute (Buffalo, NY) for the construct of ARE-LUC reporter, Dr David Spencer (Baylor College of Medicine) for the construct of CMV-SEAP reporter and Dr Jorg Kaufmann for the pU6+2p110beta.shRNA construct. We also thank Mrs Marsha Danley (Department of Pathology, KUMC Hospital) and Dr Ilanchezhian Shanmugam for excellent technical assistance in IHC staining and ChIP assay, respectively. This study was supported by KU William L Valk Endowment and Kansas Masonic Foundation through KU Cancer Center pilot grant. This work was also partially supported by a KU-NIH COBRE grant (1P20RR15563) from the National Center for Research Resources (NIH-NCRR), Department of Defense New Investigator Award (DAMD17-03-1-0121) and Idea Development Award (W81XWH-04-1-0214) to Dr Benyi Li.

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Authors and Affiliations

  1. Department of Medical Oncology, The First Affiliated Hospital, Xi'An Jiaotong University, College of Medicine, Xi'An, China

    Q Zhu & B Li

  2. Department of Urology, The University of Kansas Medical Center, Kansas City, KS, USA

    Q Zhu, H Youn, J Tang, J B Thrasher & B Li

  3. Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS, USA

    O Tawfik, K Dennis & B Li

  4. Department of Molecular and Integrated Physiology, The University of Kansas Medical Center, Kansas City, KS, USA

    P F Terranova & B Li

  5. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    J Du

  6. INSERM U563, Bat C, Hôpital Purpan, Toulouse, France

    P Raynal

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Correspondence to B Li.

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Zhu, Q., Youn, H., Tang, J. et al. Phosphoinositide 3-OH kinase p85α and p110β are essential for androgen receptor transactivation and tumor progression in prostate cancers. Oncogene 27, 4569–4579 (2008). https://doi.org/10.1038/onc.2008.91

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