COMPARATIVE STUDY
JOURNAL ARTICLE

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
15371835

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.

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