Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival.
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.
Shanmugam
I
I
Department of Urology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
Cheng
G
G
Terranova
P F
PF
Thrasher
J B
JB
Thomas
C P
CP
Li
B
B
D000728:Androgens / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D000099184:Serum-Glucocorticoid Regulated Kinases
D000728:Androgens; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D000099184:Serum-Glucocorticoid Regulated Kinases; C410798:AR protein, human