Influence of cell type on the steroidogenic potential and basal cyclic AMP levels of ras-oncogene-transformed rat cells

Abstract

Transformation with ras oncogenes causes loss, maintenance or modulation of differentiation, depending on the developmental history of the target cells. In the present study, we examined steps in signal transduction that may underlie some of this variation, using steroidogenic cells of adult rats as the model system. Steroidogenesis in normal cells is regulated by cyclic AMP and protein kinase A (the cAMP/PKA pathway). We showed previously that transformation with v-Ki-ras induces constitutive progesterone secretion in ovarian and adrenocortical cells that are normally steroidogenic (ovarian granulosa and adrenal glomerulosa cells) and also in developmentally related cells that are normally nonsteroidogenic (ovarian surface epithelium and adrenal capsular fibroblasts), but not in unrelated nonsteroidogenic cells, such as muscle fascia fibroblasts and peritoneal mesothelium. In the present study, basal cAMP levels in all transformed ovarian and adrenal cell-lines were increased over basal levels in normal cells, and of transformed muscle fascia and mesothelial cell-lines. As in normal cells, transformation-induced steroidogenesis was stimulated by cAMP and was PKA dependent. A comparison of malignancy-related characteristics showed that transformed cells from nonsteroidogenic organs were more tumorigenic in vivo and less sensitive to growth inhibition by cAMP in vitro than transformed ovarian and adrenocortical cells. The results show that the abnormal, constitutive steroidogenesis induced by the viral form of the Kirsten ras oncogene (v-Ki-ras) in certain cell types is associated with tissue-specific increases in basal cAMP levels. Thus, although the ras oncogenes function primarily through other signal transduction pathways, transformation with ras oncogenes alters PKA-mediated signal transduction in a manner that is developmentally determined. Since characteristics related to tumorigenicity are influenced by cAMP/PKA action, such differentiation-related changes in cAMP may be responsible for some of the organ-specific phenotypic variation among neoplasms expressing activated ras oncogenes.