Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins.
Androgen receptor (AR) plays a central role in prostate cancer, with most tumors responding to androgen deprivation therapies, but the molecular basis for this androgen dependence has not been determined. Androgen [5alpha-dihydrotestosterone (DHT)] stimulation of LNCaP prostate cancer cells, which have constitutive phosphatidylinositol 3-kinase (PI3K)/Akt pathway activation due to PTEN loss, caused increased expression of cyclin D1, D2, and D3 proteins, retinoblastoma protein hyperphosphorylation, and cell cycle progression. However, cyclin D1 and D2 message levels were unchanged, indicating that the increases in cyclin D proteins were mediated by a post-transcriptional mechanism. This mechanism was identified as mammalian target of rapamycin (mTOR) activation. DHT treatment increased mTOR activity as assessed by phosphorylation of the downstream targets p70 S6 kinase and 4E-BP1, and mTOR inhibition with rapamycin blocked the DHT-stimulated increase in cyclin D proteins. Significantly, DHT stimulation of mTOR was not mediated through activation of the PI3K/Akt or mitogen-activated protein kinase/p90 ribosomal S6 kinase pathways and subsequent tuberous sclerosis complex 2/tuberin inactivation or by suppression of AMP-activated protein kinase. In contrast, mTOR activation by DHT was dependent on AR-stimulated mRNA synthesis. Oligonucleotide microarrays showed that DHT-stimulated rapid increases in multiple genes that regulate nutrient availability, including transporters for amino acids and other organic ions. These results indicate that a critical function of AR in PTEN-deficient prostate cancer cells is to support the pathologic activation of mTOR, possibly by increasing the expression of proteins that enhance nutrient availability and thereby prevent feedback inhibition of mTOR.
Xu
Youyuan
Y
Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
Chen
Shao-Yong
SY
Ross
Kenneth N
KN
Balk
Steven P
SP
D055372:AMP-Activated Protein Kinases; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D056741:Cyclin D; D016213:Cyclins / Q000096:biosynthesis*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011944:Receptors, Androgen / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases
D055372:AMP-Activated Protein Kinases; D056741:Cyclin D; D016213:Cyclins; D013196:Dihydrotestosterone; D009097:Multienzyme Complexes; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D011944:Receptors, Androgen; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human