PMID- 15371835
OWN - NLM
STAT- MEDLINE
DCOM- 20041102
LR  - 20191210
IS  - 0022-5347 (Print)
IS  - 0022-5347 (Linking)
VI  - 172
IP  - 4 Pt 1
DP  - 2004 Oct
TI  - Mammalian target of rapamycin and 3-phosphatidylinositol 3-kinase pathway 
      inhibition enhances growth inhibition of transforming growth factor-beta1 in 
      prostate cancer cells.
PG  - 1333-7
AB  - PURPOSE: Serum transforming growth factor (TGF)-beta1 is elevated in patients 
      with metatatic prostate cancer. Although growth inhibitory in normal prostate 
      epithelial cells, cancer cells are often resistant to TGF-beta1. The role of 
      phosphatidylinositol 3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) 
      signaling in TGF-beta1 resistance was studied in prostate cancer cell lines. 
      MATERIALS AND METHODS: PC3 and LNCaP human prostate cancer cell lines were 
      exposed for 72 hours to rapamycin (mTOR inhibition), LY294002 (PI3K/AKT 
      inhibition) and TGF-beta1 in a proliferation (WST-1) assay. A TGF-beta1 receptor 
      II, stably transfected LNCaP cell line was used (LNCaP-RII). TGF-beta1/SMAD (Sma 
      and MAD [mothers-against-decapentaplegic]homologue) signaling was assessed using 
      the pGL3-SBE4-luc (SBE4) reporter plasmid. Immunoblotting and immunocytochemistry 
      were applied to evaluate phosphorylated Smad and E-cadherin expression in 
      relation to mTOR inhibition and TGF-beta1 exposure. RESULTS: In PC3 and LNCaP-RII 
      cells mTOR and PI3K/AKT inhibition caused TGF-beta1 to become inhibitory for 
      growth. The synergistic effect was associated with the increased expression of 
      phosphorylated Smad and induction of SBE4 reporter plasmid expression. E-cadherin 
      in PC3 cells increased upon mTOR inhibition and TGF-beta1 exposure. CONCLUSIONS: 
      Inhibition of growth signaling through PI3K/AKT/mTOR renders prostate cancer 
      cells sensitive to TGF-beta1 induced growth inhibition.
FAU - van der Poel, H G
AU  - van der Poel HG
AD  - Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - United States
TA  - J Urol
JT  - The Journal of urology
JID - 0376374
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Chromones)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Transforming Growth Factor beta)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 76W6J0943E (Flutamide)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Cell Division/*drug effects
MH  - Cell Line, Tumor
MH  - Chromones/pharmacology
MH  - Drug Interactions
MH  - Flutamide/pharmacology
MH  - Humans
MH  - Male
MH  - Morpholines/pharmacology
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Prostatic Neoplasms/*pathology
MH  - Signal Transduction/*drug effects
MH  - Sirolimus/*pharmacology
MH  - Stimulation, Chemical
MH  - Transforming Growth Factor beta/*physiology
MH  - Tumor Cells, Cultured/*drug effects/pathology
EDAT- 2004/09/17 05:00
MHDA- 2004/11/04 09:00
CRDT- 2004/09/17 05:00
PHST- 2004/09/17 05:00 [pubmed]
PHST- 2004/11/04 09:00 [medline]
PHST- 2004/09/17 05:00 [entrez]
AID - 00005392-200410000-00026 [pii]
AID - 10.1097/01.ju.0000138829.97838.19 [doi]
PST - ppublish
SO  - J Urol. 2004 Oct;172(4 Pt 1):1333-7. doi: 10.1097/01.ju.0000138829.97838.19.