Expression of TGFβ3 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(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(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.