Original Paper
Cell Death and Differentiation (2007) 14, 2085–2094; doi:10.1038/sj.cdd.4402227; published online 12 October 2007
Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival
Edited by JA Cidlowski
I Shanmugam1, G Cheng1, P F Terranova2,3, J B Thrasher1,3, C P Thomas4 and B Li1,2,3
- 1Department of Urology, The University of Kansas Medical Center, Kansas City, KS 66160, USA
- 2Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA
- 3Kansas Masonic Cancer Research Institute, The University of Kansas Medical Center, Kansas City, KS 66160, USA
- 4Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52246, Iowa
Correspondence: B Li, Department of Urology, KUMC Urology, 3901 Rainbow Blvd, Lied 1042, Kansas City, KS 66160, USA. Tel: +1 913 588 4773; Fax: +1 913 588 7625; E-mail: bli@kumc.edu
Received 20 February 2007; Revised 20 August 2007; Accepted 28 August 2007; Published online 12 October 2007.
Abstract
Androgen receptor (AR) is a critical factor in the development and progression of prostate cancer. We and others recently demonstrated that eliminating AR expression leads to apoptotic cell death in AR-positive prostate cancer cells. To understand the mechanisms of AR-dependent survival, we performed a genome-wide search for AR-regulated survival genes. We found that serum/glucocorticoid-induced protein kinase-1 (SGK-1) mRNA levels were significantly upregulated after androgen stimulation, which was confirmed to be AR dependent. Promoter analysis revealed that the AR interacted with the proximal and distal regions of the sgk1 promoter, leading to sgk-1 promoter activation after androgen stimulation. Functional assays demonstrated that SGK-1 was indispensable for the protective effect of androgens on cell death induced by serum starvation. SGK-1 overexpression not only rescued cells from AR small-interfering RNA (siRNA)-induced apoptosis, but also enhanced AR transactivation, even in the absence of androgen. Additionally, SGK-1 siRNA reduced AR transactivation, indicating a positive feedback effect of SGK-1 expression on AR-mediated gene expression and cellular survival. Taken together, our data suggest that SGK-1 is an androgen-regulated gene that plays a pivotal role in AR-dependent survival and gene expression.
Keywords:
SGK-1, androgen receptor, prostate cancer, survival, gene regulation
Abbreviations:
AAV, adeno-associated virus; AR, androgen receptor; ARHP, AR hairpin; cDNA, complementary DNA; ChIP, chromatin immunoprecipitation; cFBS, charcoal-stripped FBS; CMV, cytomegalovirus; CSDX, Casodex; FBS, fetal bovine serum; GRE, glucocorticoid response element; I
B-
, I kappa B-alpha; IKK
, IB kinase ; NF-B, nuclear factor-B; PB, probasin; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PI3K, phosphoinositide 3–kinases; PKB, protein kinase B; PSA, prostate-specific antigen; RT, reverse transcription; SE, standard error; SEAP, secreted alkaline phosphatase; SGK-1, serum/glucocorticoid-induced protein kinase-1; siRNA, small-interfering RNA; SRE, steroid response element; TBS-T, Tris-buffered saline/Tween-20
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