Tumor suppressor activity of glucocorticoid receptor in the prostate

Abstract

Glucocorticoids are extensively used in combination chemotherapy of advanced prostate cancer (PC). Little is known, however, about the status of the glucocorticoid receptor (GR) in PC. We evaluated over 200 prostate samples and determined that GR expression was strongly decreased or absent in 70-85% of PC. Similar to PC tumors, some PC cell lines, including LNCaP, also lack GR. To understand the role of GR, we reconstituted its expression in LNCaP cells using lentiviral approach. Treatment of LNCaP-GR cells with the glucocorticoids strongly inhibited proliferation in the monolayer cultures and blocked anchorage-independent growth. This was accompanied by upregulation of p21 and p27, down-regulation of cyclin D1 expression and c-Myc phosphorylation. Importantly, the activation of GR resulted in normalized expression of PC markers hepsin, AMACR, and maspin. On the signaling level, GR decreased expression and inhibited activity of the MAP-kinases (MAPKs) including p38, JNK/SAPK, Mek1/2 and Erk1/2. We also found that activation of GR inhibited activity of numerous transcription factors (TF) including AP-1, SRF, NF-kappaB, p53, ATF-2, CEBPalpha, Ets-1, Elk-1, STAT1 and others, many of which are regulated via MAPK cascade. The structural analysis of hepsin and AMACR promoters provided the mechanistic rationale for PC marker downregulation by glucocorticoids via inhibition of specific TFs. Our data suggest that GR functions as a tumor suppressor in prostate, and inhibits multiple signaling pathways and transcriptional factors involved in proliferation and transformation.

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

“…The GR␤ isoform, however, lacks helix 12 of the C terminus in the ligand-binding domain and cannot bind GCs (11). The anti-proliferative properties of GCs are mediated by GR␣, which have been attributed to elevation of cell cycle arrest proteins, p27 and p21 (12,13). A reduction in GR␣ in murine macrophages results in enhanced growth and decreased expression of p27 (14).…”

Role of multi-hnRNP nuclear complex in regulation of tumor suppressor ANXA7 in prostate cancer cells

“…Remarkably, this pattern remains specific for PrEC, indicating aberrant regulation of the ANXA7-promoter activity in cancer cells. Most remarkably, the lowest activity for all ANXA7-promoter segments (Po0.05 in most comparisons including PrEC) is found in LNCaP, which lack functional signaling through two major nuclear regulators, androgen (AR) and glucocorticoid (GR) receptors (Yemelyanov et al, 2007).…”

“…A relatively abundant active GR can function as a tumor suppressor (Yemelyanov et al, 2007) by inhibiting multiple pathways in cell transformation. As stress response mediators, glucocorticoids are linked to PPAR signaling that affects lipid pathways (including arachidonate cascade) in energy homeostasis (Rizzo and Fiorucci, 2006).…”

11β-hydroxysteroid dehydrogenase type II: a Potential target for prevention of colonic tumorigenesis

“…Recent studies found the inhibitory effect of GCs to COX-2 could suppress solid tumor growth, regress tumor mass, and prevent metastasis by blocking angiogenesis [19,20]. However, the undesirable side effects of immunosuppression limit their application in cancer chemoprevention and chemotherapy.…”