Transmembrane redox in control of cell growth. Stimulation of HeLa cell growth by ferricyanide and insulin.

The impermeable electron acceptor ferricyanide stimulates the growth of HeLa cells in the absence of serum and increases cell replication with limiting amounts of serum (0.75%). Maximum growth stimulation occurs at low ferricyanide concentration from 0.01 to 0.1 mM. Higher ferricyanide concentrations inhibit growth on serum. Addition of insulin enhances the stimulating effect of ferricyanide. Increase in the transplasmalemma electron transport activity in the presence of insulin is also observed by measuring the rate of ferricyanide reduction by cells. There is a close correlation between insulin stimulation of ferricyanide reduction and insulin induction of cell proliferation and attachment. In addition to ferricyanide, the growth response is observed with other impermeable oxidants, such as indigotetrasulfonate and hexaamine ruthenium III, which are reduced by the transplasma membrane electron transport system. Inactive oxidants such as cytochrome c do not stimulate cell growth. Ferrocyanide does not stimulate growth. We propose that electron flow through the transplasma membrane electron transport system stimulates growth and that insulin acts to increase that flow.