Antiproliferative activity of KCl contributes to EGF-induced neurite outgrowth in PC12 cells

Combinations of epidermal growth factor (EGF) and KCl stimulate differentiation in PC12 cells, independent of extracellular calcium [Mark et al., Stimulation of neurite outgrowth in PC12 cells by EGF and KCl depolarization: a Ca2+-independent phenomenon, J. Cell Biol., 130 (1995) 701-710]. Since EGF is a proliferative agent that normally does not stimulate differentiation of PC12 cells, we hypothesize that KCl plus EGF may cause differentiation because of the anti-proliferative activity of KCl. Here we report that treatment of PC12 cells with KCl plus EGF resulted in a significant decrease in proliferation and DNA synthesis compared with cells treated with EGF alone. In addition, KCl significantly reduced the EGF-induced expression of cell cycle progression factors cdk2, cdk4, cyclin B1 and PCNA. These data suggest that the anti-proliferative activity of KCl may convert EGF from a proliferative factor to a progression factor.