Different signals mediate transforming growth factor-beta 1-induced growth inhibition and extracellular matrix production in prostatic carcinoma cells.
The effects of transforming growth factor-beta 1 (TGF-beta 1) on a human prostatic carcinoma cell line PC-3, and its subclone PC-3U, were investigated. Dose-dependent inhibition of [3H]thymidine incorporation in PC-3U cells was observed by addition of TGF-beta 1, although only 50% inhibition was obtained by high concentrations (12 nM) of TGF-beta 1. The growth inhibitory effects of TGF-beta 1 on PC-3 cells was insignificant. When 0.3 ng/ml of phorbol 12-myristate 13-acetate (PMA) was added together with TGF-beta 1, TGF-beta 1 inhibited growth of PC-3 cells (about 50% inhibition), and the growth inhibitory activity of TGF-beta 1 in PC-3U cells was enhanced (more than 90% inhibition). Affinity crosslinking studies revealed that both cell lines possess all of the three described forms of TGF-beta receptors. The intensities of the crosslinked bands were weaker in the PC-3 cells than in PC-3U cells, and those were not increased by the addition of PMA. The expression of the TGF-beta type II receptor mRNA did not change after the addition of PMA or TGF-beta 1. These results suggest that the effects of PMA involved downstream components of the signal transduction pathway of TGF-beta 1. TGF-beta 1 is known to stimulate the production of extracellular matrix proteins and to induce changes in the expression of nuclear transcription factor genes. In both PC-3 and PC-3U cells, TGF-beta 1 was found to stimulate the induction of fibronectin and plasminogen activator inhibitor-1 and the expression of junB mRNA, and PMA did not affect these responses. Thus, PC-3 and PC-3U cells, which are partially resistant to the growth inhibitory activity of TGF-beta 1, could still respond to TGF-beta 1 by extracellular matrix production, independent of PMA action. These results suggest that different signalling pathways mediate TGF-beta 1-induced growth inhibition and stimulation of extracellular matrix accumulation in these cells.
Franzén
P
P
Ludwig Institute for Cancer Research, Biomedical Center, Uppsala, Sweden.
Ichijo
H
H
Miyazono
K
K
D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects*; D004351:Drug Resistance; D005353:Fibronectins / Q000096:biosynthesis*; D005355:Fibrosis / Q000503:physiopathology; D016758:Genes, jun / Q000187:drug effects; D006801:Humans; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000503:physiopathology; D012313:RNA / Q000032:analysis; D011956:Receptors, Cell Surface / Q000032:analysis; D018125:Receptors, Transforming Growth Factor beta; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D012313:RNA; D013755:Tetradecanoylphorbol Acetate; D013936:Thymidine