Mammalian target of rapamycin and 3-phosphatidylinositol 3-kinase pathway inhibition enhances growth inhibition of transforming growth factor-beta1 in prostate cancer cells

H G van der Poel
Journal of Urology 2004, 172 (4 Pt 1): 1333-7

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.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"