title: SGK3 is an androgen-inducible kinase promoting prostate cancer cell proliferation through activation of p70 S6 kinase and up-regulation of cyclin D1.
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.
authors.affiliation: Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010.
authors.forename: Yuanzhong
authors.initials: Y
authors.lastname: Wang
authors.forename: Dujin
authors.initials: D
authors.lastname: Zhou
authors.forename: Shiuan
authors.initials: S
authors.lastname: Chen
mesh_terms: D000728:Androgens / Q000494:pharmacology / Q000502:physiology; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004789:Enzyme Activation; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011944:Receptors, Androgen / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000728:Androgens; D019938:Cyclin D1; D013196:Dihydrotestosterone; D017346:Protein Serine-Threonine Kinases; D011944:Receptors, Androgen; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C530104:CCND1 protein, human; C403243:SGK3 protein, human; D000099184:Serum-Glucocorticoid Regulated Kinases
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