PMID- 16885382
OWN - NLM
STAT- MEDLINE
DCOM- 20060928
LR  - 20211203
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 15
DP  - 2006 Aug 1
TI  - Androgens induce prostate cancer cell proliferation through mammalian target of 
      rapamycin activation and post-transcriptional increases in cyclin D proteins.
PG  - 7783-92
AB  - 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.
FAU - Xu, Youyuan
AU  - Xu Y
AD  - Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, 
      Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, 
      USA.
FAU - Chen, Shao-Yong
AU  - Chen SY
FAU - Ross, Kenneth N
AU  - Ross KN
FAU - Balk, Steven P
AU  - Balk SP
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Cyclin D)
RN  - 0 (Cyclins)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Androgen)
RN  - 08J2K08A3Y (Dihydrotestosterone)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases
MH  - Cell Growth Processes/physiology
MH  - Cell Line, Tumor
MH  - Cyclin D
MH  - Cyclins/*biosynthesis
MH  - Dihydrotestosterone/*pharmacology
MH  - Enzyme Activation
MH  - Humans
MH  - Male
MH  - Multienzyme Complexes/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Prostatic Neoplasms/genetics/*metabolism/*pathology
MH  - Protein Kinases/*metabolism
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Receptors, Androgen/*metabolism
MH  - Ribosomal Protein S6 Kinases
MH  - TOR Serine-Threonine Kinases
EDAT- 2006/08/04 09:00
MHDA- 2006/09/29 09:00
CRDT- 2006/08/04 09:00
PHST- 2006/08/04 09:00 [pubmed]
PHST- 2006/09/29 09:00 [medline]
PHST- 2006/08/04 09:00 [entrez]
AID - 66/15/7783 [pii]
AID - 10.1158/0008-5472.CAN-05-4472 [doi]
PST - ppublish
SO  - Cancer Res. 2006 Aug 1;66(15):7783-92. doi: 10.1158/0008-5472.CAN-05-4472.