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


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.
van der Poel
H G
HG
Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004347:Drug Interactions; D005485:Flutamide / Q000494:pharmacology; D006801:Humans; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D013268:Stimulation, Chemical; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D002867:Chromones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016212:Transforming Growth Factor beta; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D005485:Flutamide; D020123:Sirolimus