Induction of process outgrowth in vertebrate and invertebrate cell lines by a 2-pyridinyl thiosemicarbazone.
Regulation of differentiation in cells of disparate origin is often mediated by widely differing molecular signals and receptor mechanisms. For example, two neuron-like cell lines used extensively as models for molecular control of differentiation, the steroid-sensitive Kc line from Drosophila and the polypeptide- and cyclic nucleotide-sensitive PC12 line from rat, share no obvious growth factor or hormone receptors. However, we have found that a thiosemicarbazone, 1-pyrrolidinecarbothioic acid [1-(2-pyridinyl)ethylidene] hydrazide, one of a class of synthetic antineoplastic agents, induces process outgrowth - a marker of cellular differentiation - in cells of both of these lines. Moreover, the thiosemicarbazone induces process outgrowth in cells of mutant clones of these lines that are refractory to treatment with growth factors or hormones. Activity of the thiosemicarbazone is dependent upon the alpha-(N)-heterocyclic ring. These findings show that the 2-pyridinyl thiosemicarbazone mimics the effects of diverse epigenetic factors in inducing process outgrowth similar to that seen in cellular differentiation of these cell lines induced by natural regulators. Regulation may be by a mechanism, common to both invertebrate and vertebrate cells, which occurs downstream from the receptors that have been previously shown to mediate epigenetically induced differentiation.