PROLIFERATION OF THE MURINE CORTICOTROPIC TUMOR-CELL LINE ATT20 IS AFFECTED BY HYPOPHYSIOTROPHIC HORMONES, GROWTH-FACTORS AND GLUCOCORTICOIDS

In pituitary-dependent hyperadrenocorticism (Cushing's disease), the d isturbed regulation of ACTH secretion is associated with neoplastic tr ansformation of corticotropic cells. As these two phenomena are almost indissolubly connected, it is of prime importance to elucidate the fa ctor(s) that induce corticotropic cell proliferation. Here we report o n the effects of hypophysiotrophic hormones and intrapituitary growth factors on the proliferation and hormone secretion of the murine corti cotropic tumour cell line AtT20/D16v, as measured by DNA content, and ACTH concentration in culture media. In addition, sensitivity to the i nhibitory effect of cortisol was assessed under various conditions. Co rticotropin releasing hormone (CRH) and vasopressin (AVP) induced prol iferation of AtT20-cells. In contrast to that caused by AVP, the CRH-i nduced proliferation was associated with increased ACTH secretion, whi ch could be inhibited by cortisol. Insulin-like growth factor-I (IGF-I ), epidermal growth factor (EGF) and basic fibroblast growth factor (b FGF) also stimulated the proliferation of AtT20-cells. The proliferati on of AtT20-cells was significantly inhibited by cortisol in all tests . The IGF-I-induced proliferation was the least sensitive to inhibitio n by cortisol. The growth factors did not stimulate ACTH secretion but IGF-I differed in that it prevented the inhibition of basal ACTH secr etion by cortisol. Additional experiments (Western ligand blot analysi s) concerning the relative insensitivity of IGF-I induced proliferatio n to inhibition by cortisol revealed that IGF-I increased the concentr ation of a 29 kDa IGF binding protein (IGFBP) in the culture medium. T he concentration of the 29 kDa IGFBP was slightly decreased by cortiso l. In conclusion, the proliferation of AtT20-cells can be stimulated b y the hypophysiotrophic hormones CRH and AVP and by the intrapituitary growth factors IGF-I, EGF and bFGE. Both basal and stimulated prolife ration are sensitive to inhibition by cortisol, although this effect i s remarkably low in the presence of IGF-I. IGF-I induced the secretion of a 29 kDa IGFBP, which might mediate the IGF-I effects by its intri nsic mitogenic properties. In addition to loss of sensitivity to endog enous glucocorticoids, high IGF-I concentrations may be a prerequisite for clonal expansion of pituitary corticotropes.