Effect of tumor promoters on the response of cultured embryonic chick ganglia to nerve growth factor.

The tumor-promoting plant diterpene 12-O-tetradecanoyl-phorbol-13-acetate (TPA) inhibits nerve growth factor (NGF)-provoked neurite outgrowth in cultured embryonic chick sensory and sympathetic ganglia. Other plant diterpenes that are tumor promoters on the mouse skin carcinogenesis system also inhibit ganglia response to NGF, but structurally related nonpromoting compounds are inactive. There is no evidence that the inhibitory effect of TPA is due to cytotoxicity. In fact, it appears that TPA can enhance the survival of neuronal and nonneuronal cells in culture. Although neurite outgrowth is prevented, established neurites do not retract in the presence of TPA. After 24 hr, ganglia can slowly overcome the block, even in the presence of fresh TPA; thus, inhibition is transient. The concentration of NGF that does induce a half-maximal neurite outgrowth response in sensory ganglia is approximately 0.6 X 10(-11) M. The antagonism of NGF by TPA is dose dependent and apparently noncompetitive. TPA concentrations that extensively inhibit neurite outgrowth do not affect the amount of 125I-labeled NGF bound to specific sites on dissociated dorsal root ganglion cells, which supports the contention that TPA acts at a stage beyond the initial interaction of the factor with its receptive site.