Genetic analysis of glucocorticoid action in neoplastic lymphoid cells

Abstract

Certain murine lymphoma cells are killed upon exposure to high physiological or pharmacological doses of glucocorticoids. This unique type of cellular response has been used for selecting a series of glucocorticoid resistant clones. Three major phenotypes of resistance have been obtained with defects in steroid binding to the specific receptor or in the nuclear interaction of the receptor-steroid complex. Cell hybridization studies suggest that these defects reside in the receptor molecule itself rather than in any modulators associated with the receptor system. These phenotypes of resistance belong to the same complementation group and thus both the steroid binding site and the nuclear interaction site of the receptor molecule appear to be contained within the same molecular unit, probably within the same polypeptide chain. Hybrids between wild-type and resistant lymphoma cells are glucocorticoid sensitive. Resistance, however, arises quite frequently in these hybrids with a rate about 100-fold higher than in the parental wild-type cells. In the majority of individual hybrid cells, steroid resistance is acquired concomitantly with the loss of one chromosome. The cytotoxic glucocorticoid effect in lymphoma cells is related to the extent of receptor saturation. A critical amount of receptor has to be complexed with steroid for the response to occur. A series of cell genetic experiments show that the cytotoxic actions of glucocorticoids and cyclic AMP, although similar in extent and kinetics, occur by independent mechanisms. Nevertheless, pretreatment of wild-type lymphoma cells with dibutyryl cyclic AMP makes the cells more susceptible to the cytotoxic action of glucocorticoids.