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PSA regulates androgen receptor expression in prostate cancer cells
BACKGROUND Prostate‐specific antigen (PSA) is a pivotal downstream target gene of the androgen receptor (AR), and a serum biomarker to monitor prostate cancer (PrCa) progression. It has been reported that PSA transactivates AR, but the mechanistic requirements of this response have not been investig...
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Published in: | The Prostate 2012-05, Vol.72 (7), p.769-776 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | BACKGROUND
Prostate‐specific antigen (PSA) is a pivotal downstream target gene of the androgen receptor (AR), and a serum biomarker to monitor prostate cancer (PrCa) progression. It has been reported that PSA transactivates AR, but the mechanistic requirements of this response have not been investigated.
METHODS
We studied the localization of PSA, AR, and Src in intracellular compartments of synthetic androgen (R1881)‐stimulated LNCaP and C4‐2B PrCa cells, using immunofluorescence and subcellular fractionation approaches. We also investigated the effect of downregulation of PSA on AR expression by immunoblotting and real‐time PCR using short hairpin RNA (shRNA) and small interfering RNA (siRNA). Src activity was analyzed by immunoblotting.
RESULTS
R1881 stimulation induced nuclear localization of both PSA and AR in LNCaP and C4‐2B PrCa cells as well as increased phosphorylation of Src. Stable shRNA or transient siRNA knockdown of PSA resulted in reduced AR protein levels as well as AR mRNA levels in C4‐2B cells. Similar to C4‐2B cells, ablation of AR levels upon silencing of PSA was also confirmed in VCaP cells, another androgen‐independent cell line. Silencing of PSA did not cause significant changes in Src activation; besides, Src regulation by integrins did not appear to affect AR transcriptional activity.
CONCLUSIONS
PSA localizes to nuclei of androgen‐stimulated PrCa cells, and controls AR mRNA and protein levels. This regulatory loop is specific for PSA, does not involve known AR activators such as Src and AKT, and may contribute to AR signaling under conditions of increasing PSA levels in patients. Prostate 72:769–776, 2012. © 2011 Wiley Periodicals, Inc. |
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ISSN: | 0270-4137 1097-0045 |
DOI: | 10.1002/pros.21482 |