Lysosomotropic amines inhibit mitogenesis induced by growth factors

The stimulation of DNA synthesis by epidermal growth factor, insulin, and serum is inhibited by a variety of alkylamines when present for the duration of the stimulatory preincubation (20-24 hr). These results contradict an earlier report [Maxfield, F. R., Davies, P. J. A., Klempner, L., Willingham, M. C. & Pastan, I. (1979) Proc. Natl. Acad. Sci. USA 76, 5731-5735] and can be explained by differences in incubation conditions. The most straightforward interpretation of our results is that the mitogenic activities of growth factors are blocked by agents that inhibit the intracellular processing of hormone-receptor complexes. Therefore, the continued internalization and degradation of growth factors or their receptors within cells may play an important role in inducing mitogenesis in cultured human fibroblasts and may explain the prolonged requirement for epidermal growth factor in the culture medium (8 hr) to elicit a mitogenic response. We also found that bacitracin, a potent inhibitor of the enzyme transglutaminase, neither prevents receptor internalization or degradation in human fibroblasts nor inhibits the mitogenic activity of epidermal growth factor. These results suggest that transglutaminase activity may not be relevant to the mechanisms of growth-factor-induced receptor internalization or mitogenesis.