APOPTOSIS INDUCED BY PROTEIN-KINASE-C INHIBITION IN A NEUROBLASTOMA CELL-LINE

The protein kinase C inhibitor bisindolylmaleimide GF109203X has a dua l effect on the behavior of tire neuroblastoma cell line Neuro-2A; whe n the inhibitor is added in conditions that induce differentiation (ab sence of serum), neurite outgrowth is potentiated in a dose-dependent manner. However, if the inhibitor is added in growth-promoting conditi ons (presence of serum), programmed cell death (apoptosis) is induced, as assessed by internucleosomal DNA cleavage and specific immunoassay s. This effect is also seen with other specific protein kinase C inhib itors. Bcl2 gene overexpression protects Neuro-2A cells from apoptosis , as has been found in other systems. We also show that calpain I, a n eutral Ca2+-activated proteinase, participates in this apoptotic pathw ay. Our results point to a key role of protein kinase C in the regulat ion of growth and differentiation in Neuro-2A cells.