ABSTRACT
We previously demonstrated that activation of the glucocorticoid receptor (GR) initiates an antiapoptotic signal in the immortalized human mammary epithelial cell line MCF10A that is dependent on the GR's transcriptional activity. In this study, we show that the survival role of GR activation extends to protecting human breast cancer cells undergoing apoptosis after growth factor deprivation. Serum and glucocorticoid-regulated kinase-1 (sgk), a gene previously identified as a direct transcriptional target of the activated GR in a rat mammary tumor cell line, was rapidly induced after GR activation in human mammary epithelial cells. Furthermore, in the absence of all growth factors, ectopic sgk expression inhibited apoptosis, suggesting that SGK is a survival kinase. Finally, kinase-dead SGK expression inhibited the protection from apoptosis usually seen after GR activation. These findings suggest that SGK is an important downstream target of GR-mediated survival signaling and that it is distinct from other survival kinases because it can be primarily regulated at the level of transcription.
Subject(s)
Apoptosis/physiology , Cell Survival/physiology , Dexamethasone/pharmacology , Gene Expression Regulation, Enzymologic , Glucocorticoids/pharmacology , Nuclear Proteins , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Receptors, Glucocorticoid/physiology , Animals , Apoptosis/drug effects , Apoptosis/genetics , Breast , Breast Neoplasms , Cell Line , Cell Survival/drug effects , Enzyme Induction , Epithelial Cells , Female , Growth Substances/pharmacology , Humans , Immediate-Early Proteins , Mifepristone/pharmacology , Protein Serine-Threonine Kinases/biosynthesis , Rats , Transcription, GeneticABSTRACT
Complex autocrine and paracrine signaling pathways control the multiple cycles of epithelial cell proliferation and involution characteristic of the human mammary gland. Activation of these pathways can lead to cell division, cell cycle arrest, apoptosis, or survival; their aberrant regulation often contributes to malignant transformation. In this report, we show that glucocorticoid signals a potent survival pathway in the immortalized human mammary epithelial cell line MCF10A. Withdrawal of glucocorticoid from defined media triggers apoptosis, despite the presence of epidermal growth factor and insulin. Apoptosis is accelerated by ectopic expression of c-Myc and blocked by overexpression of Bcl2. Although MCF10A cells can undergo apoptosis after CD95/Fas receptor activation, cell death caused by glucocorticoid withdrawal is independent of CD95/ Fas receptor signaling. The mechanism through which glucocorticoid inhibits apoptosis is also independent of phosphatidylinositol 3-kinase activity and its downstream target Akt, thus establishing the existence of a novel epithelial cell survival pathway mediated by glucocorticoids.
