Differential effects of 12-O-tetradecanoyl-13-phorbol acetate (TPA) on growth, migration and invasion of a human glioma cell line.

To evaluate the effects of protein kinase C (PKC) activation on a human glioma cell line (GaMG), this study examined the effects of the phorbol ester 12-O-tetradecanoyl-13-phorbol acetate (TPA) on the tumor properties proliferation, migration and invasion. GaMG monolayer growth was reduced by 30% (p < 0.05) in the presence of TPA and, concomitantly, cells accumulated in the G2M phase of the cell cycle as determined by flow-cytometric analyses. In studies of directional migration of cells from GaMG spheroids, low concentrations of TPA increased the area of migration by 60% (p < 0.005). The effects at higher concentrations of the phorbol ester were still present but less pronounced. Glioma invasion was assessed with a glioma spheroid/brain aggregate co-culture technique and revealed TPA-induced enhancement of the invasive process (p < 0.005) at low concentrations of the phorbol ester. Down-regulation of PKC by passaging the cells in a TPA containing medium significantly decreased the migratory response to TPA. Moreover, the PKC inactive phorbol ester 4-alpha-phorbol-12,13-didecanoate had no effect on the migratory response of GaMG cells. It is concluded that metabolic pathways under the control of PKC may play an important role in the control of glioma growth, migration and invasion. The effects of PKC activation are probably dependent on the growth conditions. Studies on PKC activation under different culture conditions in three-dimensional systems are required to evaluate further the role of PKC in glioma biology.