Abstract
Glucocorticoid receptor (GR) is emerging as a key driver of prostate cancer (PCa) progression and therapy resistance in the absence of androgen receptor (AR) signaling. Acting as a bypass mechanism, GR activates AR-regulated genes, although GR-target genes contributing to PCa therapy resistance remain to be identified. Emerging evidence also shows that African American (AA) men, who disproportionately develop aggressive PCa, have hypersensitive GR signaling linked to cumulative stressful life events. Using racially diverse PCa cell lines (MDA-PCa-2b, 22Rv1, PC3, and DU145) we examined the effects of glucocorticoids on the expression of two stress oncoproteins associated with PCa therapy resistance, Clusterin (CLU) and Lens Epithelium-Derived Growth Factor p75 (LEDGF/p75). We observed that glucocorticoids upregulated LEDGF/p75 and CLU in PCa cells. Blockade of GR activation abolished this upregulation. We also detected increased GR transcript expression in AA PCa tissues, compared to European American (EA) tissues, using Oncomine microarray datasets. These results demonstrate that glucocorticoids upregulate the therapy resistance-associated oncoproteins LEDGF/p75 and CLU, and suggest that this effect may be enhanced in AA PCa. This study provides an initial framework for understanding the contribution of glucocorticoid signaling to PCa health disparities.
Highlights
A pressing implication is that glucocorticoid therapy presently administered to PCa patients as a standard of care could be detrimental under certain clinical conditions[2,5,10,11,12]
Consistent with our immunoblotting results, we observed a significant increase in LEDGF/p75 and CLU transcript expression in MDA-PCa-2b, 22Rv1, and PC3 cells exposed to 10 nM Dex, compared to untreated cells, with significant decrease in transcript expression in DU145 cells (Fig. 3A–D)
While key stress oncoproteins associated with increased PCa cell survival in the presence of environmental stressors such as chemotherapeutic drugs have been identified and at times targeted in pre-clinical and clinical studies (e.g., CLU, LEDGF/p75, HSP27, PRDXs), there remains a need to understand the potential contribution of glucocorticoid signaling to the activation and upregulation of these proteins
Summary
A pressing implication is that glucocorticoid therapy presently administered to PCa patients as a standard of care could be detrimental under certain clinical conditions[2,5,10,11,12]. While the ability of GR to activate AR-target genes in the context of mCRPC has been demonstrated[2,5,6,7,8,9,10,11,12], there is a need to identify specific genes driven by GR signaling that have been previously linked to taxane chemotherapy. This is critical to our understanding of mechanisms by which GR may induce taxane resistance, and the identification of potential therapeutic targets. The role of CLU in mCRPC resistance to DTX is well defined[18,20,22,25,37]
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