Abstract
Glucocorticoids are used during prostate cancer (PCa) treatment. However, they may also have the potential to drive castration resistant prostate cancer (CRPC) growth via the glucocorticoid receptor (GR). Given the association between inflammation and PCa, and the anti-inflammatory role of heme oxygenase 1 (HO-1), we aimed at identifying the molecular processes governed by the interaction between HO-1 and GR. PCa-derived cell lines were treated with Hemin, Dexamethasone (Dex), or both. We studied GR gene expression by RTqPCR, protein expression by Western Blot, transcriptional activity using reporter assays, and nuclear translocation by confocal microscopy. We also evaluated the expression of HO-1, FKBP51, and FKBP52 by Western Blot. Hemin pre-treatment reduced Dex-induced GR activity in PC3 cells. Protein levels of FKBP51, a cytoplasmic GR-binding immunophilin, were significantly increased in Hemin+Dex treated cells, possibly accounting for lower GR activity. We also evaluated these treatments in vivo using PC3 tumors growing as xenografts. We found non-significant differences in tumor growth among treatments. Immunohistochemistry analyses revealed strong nuclear GR staining in almost all groups. We did not observe HO-1 staining in tumor cells, but high HO-1 reactivity was detected in tumor infiltrating macrophages. Our results suggest an association and crossed modulation between HO-1 and GR pathways.
Highlights
Glucocorticoid receptor (GR) activation, mediated by the binding of glucocorticoids, regulates the expression of inflammatory factors
The aim of this study was to analyse the interaction between GR and heme oxygenase 1 (HO-1) and to identify the molecular processes governed by the association between these two proteins in prostate cancer (PCa)
Hemin-induced HO-1 over-expression was confirmed by Western Blot and Reverse Transcription–Quantitative PCR (RTqPCR) (Figure 1B and Supplemental Figure S1, respectively)
Summary
Glucocorticoid receptor (GR) activation, mediated by the binding of glucocorticoids, regulates the expression of inflammatory factors. FKBP51 is released from GR and replaced by FKBP52 which, in turn, recruits dynein/dynactin [1]. This immunophilin exchange assemblies the molecular machinery for the efficient and fast nuclear transport of GR. GR is upregulated in castration-resistant tumors and its over-expression is involved in the development of abiraterone and enzalutamide resistance [2], bypassing androgen receptor (AR) blockage and regulating a subset of distinguishable AR target genes [3]. The GR upregulation can be explained by the lack of AR binding to a negative androgen response element in the GR promoter [4]
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