Abstract
Androgen receptor (AR) plays a central role in prostate cancer (PCa) growth, with androgen deprivation or AR down-regulation causing cell-cycle arrest and accumulation of the p27 cyclin-dependent kinase inhibitor. The molecular basis for this AR regulation of cell-cycle progression remains unclear. Here we demonstrate that androgen can rapidly reduce p27 protein in PCa cells by increasing its proteasome-mediated degradation. This rapid androgen-stimulated p27 degradation was mediated by AKT through the phosphorylation of p27 T157. Significantly, androgen increased TORC2-mediated AKT S473 phosphorylation without affecting the PDK1-mediated AKT T308 phosphorylation or TORC1 activity. The TORC2 activation was further supported by enhanced mTOR/RICTOR association and increased phosphorylation of additional TORC2 substrates, SGK1 and PKCα. The androgen-stimulated nuclear translocation of AR was associated with markedly-increased nuclear SIN1, a critical component of TORC2. Finally, the androgen-mediated TORC2/AKT activation targets a subset of AKT substrates including p27 and FOXO1, but not PRAS40. This study reveals a pathway linking AR to a selective activation of TORC2, the subsequent activation of AKT, and phosphorylation of a discrete set of AKT substrates that regulate cellular proliferation and survival. These findings establish that TORC2 can function as a central regulator of growth in response to signals that are distinct from those regulating TORC1, and support efforts to target TORC2 for cancer therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation*
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Cell Survival
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Cyclin-Dependent Kinase Inhibitor p27 / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism*
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism
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Male
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Mice
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Phosphorylation / genetics
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism*
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Prostatic Neoplasms / therapy
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Protein Kinase C-alpha / genetics
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Protein Kinase C-alpha / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proteolysis*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Rapamycin-Insensitive Companion of mTOR Protein
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism*
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Carrier Proteins
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Cdkn1b protein, mouse
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Crtc1 protein, mouse
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Crtc2 protein, mouse
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Immediate-Early Proteins
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Rapamycin-Insensitive Companion of mTOR Protein
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Receptors, Androgen
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Trans-Activators
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Transcription Factors
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rictor protein, mouse
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stress-activated protein kinase-interacting protein, mouse
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Cyclin-Dependent Kinase Inhibitor p27
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mTOR protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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serum-glucocorticoid regulated kinase
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Prkca protein, mouse
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Protein Kinase C-alpha