Is the glucocorticoid receptor a key player in prostate cancer?: A literature review

Abstract

Glucocorticoids act through the glucocorticoid receptor (GR) and exert pleiotropic effects in different cancer types. In prostate cancer cells, GR and androgen receptor (AR) share overlapping transcriptomes and cistromes. Under enzalutamide treatment, GR signaling can bypass AR activation and promote castration resistance via the expression of a subset of AR-target genes. However, GR-dependent growth under enhanced antiandrogen inhibition occurs only in a subset of primed cells. On the other hand, glucocorticoids have been used successfully in the treatment of prostate cancer for many years. In the context of AR signaling, GR competes with AR for DNA-binding and has the potential to halt the proliferation rate of prostate cancer cells. Their target genes overlap by <50% and they execute unique functions in vivo. In addition, even when AR and GR upregulate the same transcriptional target gene, the effect might not be identical in magnitude. Besides being able to drive tumor proliferation, GR is also a key player in prostate cancer cell survival. Stimulation of GR activity can undermine the effects of enhanced antiandrogen treatment, chemotherapy and radiotherapy. GR activation in prostate cancer can increase prosurvival gene expression. Identifying the full spectrum of GR activity will inform the optimal use of glucocorticosteroids in prostate cancer. It will also determine the best strategies to target the protumorigenic effects of GR.

Glucocorticoid Receptor and β-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance

“…Several mechanisms contributing to ARSI resistance in mCRPC have been identified, including reactivation of AR signaling through AR amplification, mutations, co-regulator activity, or expression of splice variants such as AR variant 7 (AR-V7) [ 7 , 8 , 9 , 10 ]. Signaling through the glucocorticoid receptor (GR, encoded by the NR3C1 gene) has also emerged as a major contributor to ARSI resistance [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. GR is closely related to AR, as both steroid receptors belong to the nuclear receptor superfamily and share significant structural similarity and transcriptomic overlap [ 11 , 12 ].…”

“…The induction of GR during ARSI treatment appears to be mediated by the loss of TLE3, a transcriptional co-repressor that regulates AR-mediated repression of GR [ 21 ], as well as the activation of the PI3K/AKT signaling pathway [ 15 ]. GR signaling has also been linked to DTX resistance in PCa, possibly by activating anti-apoptotic Bcl-2 family members and Mono Amine Oxidase-A [ 16 , 22 ]. In addition, GR silencing in diverse PCa cell lines reduces the capacity for cancer stem cell (CSC)-like tumorsphere formation [ 14 ], consistent with evidence that PCa stemness contributes to DTX resistance [ 23 , 24 , 25 , 26 ].…”

Phase 1 Study to Evaluate the Safety of Reducing the Prophylactic Dose of Dexamethasone around Docetaxel Infusion in Patients with Prostate and Breast Cancer

“…In recent years, it has been established that glucocorticoid receptors (GRs) may be involved in the development of castration-resistant prostate cancer (CRPC) [ 20 , 21 ]. The upregulation of the GR may drive tumor proliferation and possibly lead to resistance to antiandrogen therapies [ 22 ]. As a consequence, the use of dexamethasone and other corticosteroids may contribute to tumor progression in prostate cancer [ 23 , 24 ].…”

Glucocorticoid Receptor and Ovarian Cancer: From Biology to Therapeutic Intervention

“…Moreover, in patient-derived xenograft (PDX) models, GR activation resulted in increased expression of the transmembrane receptor tyrosine protein kinase (ROR1), which promotes metastatic colonization and reduces cells survival via the activation of the Wnt and hippo pathways [ 41 ]. Similarly to BC, the GR duality of action has also been observed in prostate cancer (PC) [ 10 , 42 , 43 , 44 ]. In primary hormone-sensitive prostate cancer cell lines, GR activation reduces tumor growth and proliferation by inducing p21 and p27 expression and by downregulating the activity of cyclin D1 and c-myc [ 42 ].…”

“…In primary hormone-sensitive prostate cancer cell lines, GR activation reduces tumor growth and proliferation by inducing p21 and p27 expression and by downregulating the activity of cyclin D1 and c-myc [ 42 ]. On the other hand, GR signaling is strongly involved in the onset of resistance to anti-androgen therapies in advanced PC [ 43 ]. In particular, GR enhanced cell proliferation via activation of the signal transducer and activator of transcription 5 (STAT5), regardless of androgen receptor (AR) signaling, in castration-resistant prostate cancer (CRPC) cell lines treated with dihydrotestosterone (DHT) [ 44 ].…”