Effects of dexamethasone and phorbol myristate acetate on the induction of differentiation in mouse erythroleukemic cells by dimethyl sulfoxide, proteases, and other compounds.

Lines DS-19 and 5-86, each derived from line 745, when tested for their responses to various inducers and inhibitors of differentiation, shared some characteristics, but differed in others. In particular, DS-19 was markedly induced to differentiate by actinomycin D whereas 5-86 was only slightly affected. The patterns of the ability of PMA to influence induction and cell multiplication by various inducing agents differed in the two lines. The pattern of DEX inhibition of differentiation was similar in the two lines. Notably, DEX markedly inhibited induction due to all of the inducers tested except protease V8, actinomycin D, PGE1, and butyrate and its fatty acid analogues that were tested. DEX stimulated growth during its inhibition of induction by DMSO and many other inducers, but reduced cell multiplication in the presence of butyrate. PMA inhibited induction by most of the inducers tested in DS-19 cells except for some of the fatty acids. The inhibition by PMA generally was accompanied by cytotoxicity in DS-19 cells, but not in 5-86 cells. PMA markedly inhibited differentiation by only 5 of the inducing agents tested in 5-86 cells, but was not as cytotoxic in this line. Proteases, which have been shown to stimulate both MEL cell differentiation and growth, are inhibited with respect to their effects on differentiation, but not with respect to those on growth by DEX and/or PMA. DEX did not have the same effect on induction stimulated by the two proteases studied. Many of these findings indicate that at least some effects by inducers on cell multiplication in this system are not inextricably linked to differentiation. It is hoped that the further study of induction by proteases, which have known enzymatic activities, as well as of inhibitors of induction, will shed light on the molecular mechanism(s) of action of DMSO and other low molecular weight inducers.