Expression of TGF[beta]3 and its effects on migratory and invasive behavior of prostate cancer cells: involvement of PI3-kinase/AKT signaling pathway

Transforming growth factor-[beta] (TGF[beta]) is a secreted cytokine implicated as a factor in cancer cell migration and invasion. Previous studies have indicated that TGF[beta] isoforms may exert differential effects on cancer cells during different stages of the disease, however very little is known about the expression patterns and activity of the three isoforms in prostate cancer. Non-traditional signaling pathways including the PI3-Kinase have been associated with TGF[beta]-mediated effects on cancer cell invasion. In the present study, we have carried out expression analysis of TGF[beta] isoforms and signaling components in cell line models representing different stages of prostate cancer and studied the differential effects of specific isoforms on migratory and invasive behavior and induction of the PI3-kinase pathway. TGF[beta]1 and TGF[beta]3 were expressed in all cell lines, with TGF[beta]3 expression increasing in metastatic cell lines. Both TGF[beta]1 and TGF[beta]3 induced motility and invasive behavior in PC3 cells, however, TGF[beta]3 was significantly more potent than TGF[beta]1. TGF[beta]RI and Smad3 inhibitors blocked TGF[beta]1 and TGF[beta]3 induced motility and invasion. TGF[beta]3 caused a significant increase in pAKT^sup ser473^ in PC3 cells and PI3-kinase inhibitor LY294002 blocked TGF[beta]3 induced migration, invasion and phosphorylation of AKT. Both TGF[beta]RI and Smad3 inhibitors blocked TGF[beta]3 induced pAKT^sup ser473^. Based on these results, we conclude that TGF[beta]3 is expressed in metastatic prostate cancer cell lines and is involved in induction of invasive behavior in these cells. Furthermore, these effects of TGF[beta]3 are TGF[beta]RI and Smad3 dependent and mediated via the PI3-kinase pathway.[PUBLICATION ABSTRACT]