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.
Highlights
The specificity of the glucocorticoid receptor’s (GR)1 transcriptional activity varies widely between cell types, accounting for the diverse and sometimes opposite physiological effects of glucocorticoid in different tissues
We demonstrate that the GR survival signal is likely to be transmitted at least in part as a consequence of the transcriptional activation of sgk since (i) sgk mRNA is induced in a GR-dependent fashion immediately after glucocorticoid treatment of human mammary epithelial cells (MECs), (ii) ectopic SGK expression protects MECs from apoptosis induced by growth factor withdrawal, and (iii) expression of a kinase-dead SGK inhibits protection from apoptosis
Glucocorticoids Inhibit Apoptosis of Human Breast Cancer Cells via Activation of the GR—We previously demonstrated that GR activation initiates a potent antiapoptotic signal in the nontumorigenic MEC line MCF10A and its derivative line MCF10A-Myc
Summary
The specificity of the glucocorticoid receptor’s (GR) transcriptional activity varies widely between cell types, accounting for the diverse and sometimes opposite physiological effects of glucocorticoid in different tissues. We demonstrate that the GR survival signal is likely to be transmitted at least in part as a consequence of the transcriptional activation of sgk since (i) sgk mRNA is induced in a GR-dependent fashion immediately after glucocorticoid treatment of human MECs, (ii) ectopic SGK expression protects MECs from apoptosis induced by growth factor withdrawal, and (iii) expression of a kinase-dead SGK inhibits protection from apoptosis Taken together, these results suggest the existence of a novel GR-initiated antiapoptotic pathway that operates, at least in part, through transcriptional induction of the survival kinase gene, sgk
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