Abstract |
Both androgen and phosphatidylinositol 3-kinase (PI3K) signaling are critical for cell proliferation of androgen receptor (AR)-positive prostate cancer cells, but the underlying mechanisms are still not fully understood. Here we report that serum- and glucocorticoid-inducible kinase 3 (SGK3), a Ser/Thr kinase functioning downstream of PI3K, is an AR transcriptional target and promotes prostate cancer cell proliferation. SGK3 expression is up-regulated by androgen DHT via AR. We identified an AR-binding region at the sgk3 locus, which confers androgen responsiveness of sgk3 promoters. Interestingly, we found that androgen/AR-dependent SGK3 expression requires estrogen receptor (ER) (including both isoforms, ERα and ERβ). Depletion of ER blocked DHT-induced SGK3 expression. Functionally, knockdown of SGK3 expression significantly decreased LNCaP prostate cancer cell proliferation by inhibiting G1 to S phase cell cycle progression. We further provided evidence that SGK3 promotes p70 S6 kinase ( p70S6K) activation and increases cyclin D1 levels. In summary, our study identifies SGK3 as an AR target and provides a novel androgen-induced cell proliferation mechanism mediated by the AR-SGK3-p70S6K-cyclin D1 pathway in prostate cancer cells.
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Authors | Yuanzhong Wang, Dujin Zhou, Shiuan Chen |
Journal | Molecular endocrinology (Baltimore, Md.)
(Mol Endocrinol)
Vol. 28
Issue 6
Pg. 935-48
(Jun 2014)
ISSN: 1944-9917 [Electronic] United States |
PMID | 24739041
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Androgens
- CCND1 protein, human
- Receptors, Androgen
- Dihydrotestosterone
- Cyclin D1
- Protein Serine-Threonine Kinases
- Ribosomal Protein S6 Kinases, 70-kDa
- SGK3 protein, human
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Topics |
- Androgens
(pharmacology, physiology)
- Base Sequence
- Binding Sites
- Cell Line, Tumor
- Cell Proliferation
- Cyclin D1
(genetics, metabolism)
- Dihydrotestosterone
(pharmacology)
- Enzyme Activation
- G1 Phase Cell Cycle Checkpoints
- Humans
- Male
- Molecular Sequence Data
- Promoter Regions, Genetic
- Prostatic Neoplasms
- Protein Serine-Threonine Kinases
(physiology)
- Receptors, Androgen
(metabolism)
- Ribosomal Protein S6 Kinases, 70-kDa
(metabolism)
- Transcription, Genetic
- Transcriptional Activation
- Up-Regulation
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