Carcinogenesis Advance Access originally published online on October 10, 2006
Carcinogenesis 2007 28(3):572-583; doi:10.1093/carcin/bgl193
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Conditional Akt activation promotes androgen-independent progression of prostate cancer
1 Department of Urology, The University of Kansas Medical Center Kansas City, KA 66160, USA
2 Department of Molecular and Integrated Physiology, The University of Kansas Medical Center Kansas City, KA 66160, USA
3 Kansas Masonic Cancer Research Institute, The University of Kansas Medical Center Kansas City, KA 66160, USA
4 Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University Guangzhou 510080, China
5 Baylor College of Medicine, Department of Immunology Houston, TX, 77030.
*To whom correspondence should be addressed at: KUMC Urology, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. Tel: +1 913 588 4773; Fax: +1 913 588 7625; Email: bli{at}kumc.edu
*Correspondence may also be addressed to: Pingyi Xu, Department of Neurology, Sun Yat-sen University, Guangzhou 510080, China. Tel: 130 02087616; Email: pxu{at}kumc.edu
Aggressive androgen-independent (also termed as hormone-refractory) prostate cancer is a major clinical obstacle because there is no means to cure. Previous studies have shown that Akt activation is associated with prostate cancer progression from androgen-dependent to androgen-independent stage. However, its causative role in this process has not been established. One of the major limitations is the lack of a well-controlled inducible system to study Akt involvement. Recently, we developed a novel inducible Akt (iAKT) system based on a chemically induced dimerization (CID) approach. This system allows for conditional activation of Akt in a physiological setting. Utilizing this iAKT system, we found that Akt activation prevented cell death after serum withdrawal and promoted cell proliferation in the absence of androgen in vitro in human prostate cancer LNCaP cells, which should stop growing after androgen withdrawal or even die after serum starvation. The iAKT-induced death protection and growth promotion were further demonstrated in vivo using a transgenic mouse model that expresses the iAKT system conditionally in the prostate epithelium. Most importantly, in a mouse xenograft model derived from LNCaP cells, iAKT activation promoted tumor growth in castrated animals by enhancing cell proliferation and inhibiting apoptosis. Taken together, our data suggest that Akt activation is playing a causative role in androgen-independent progression of prostate cancer. This study provides a significant relevance of Akt-targeted therapy for hormone-refractory prostate cancers.
Abbreviations: AR, androgen receptor; BrdU, 5-bromo-2-deoxyuridine; CDK, cyclin-dependent kinase; cFBS, charcoal-stripped FBS; CID, chemically induced dimerization; IACUC, institutional Animal Care and Use Committee; iAKT, inducible Akt; IGF, insulin-like growth factor; PDK1, phosphatidylinositol-dependent kinase 1; PI3K, phosphatidylinositol 3-kinase; PH, pleckstrin-homology domain; PIN, prostatic intraepithlial neoplasia; PSA, prostate-specific antigen; PTEN, phosphatase and tensin homolog; RIPA, radio-immunoprecipitation assay
Received July 26, 2006; revised September 25, 2006; accepted October 2, 2006.
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