Emerging role of glucocorticoid receptor in castration resistant prostate cancer: A potential therapeutic target

Abstract

Glucocorticoids are used as co-medication with chemotherapy for solid tumors to reduce inflammation as well as cytotoxic side effects and are effective in easing symptoms related to chemotherapy. However, emerging evidence suggests that glucocorticoids may contribute to failure of chemotherapy and tumor progression of castration resistant prostate cancer (CRPC). Thus, in recent years, glucocorticoid signaling pathway has become an important therapeutic target for CRPC. Understanding the exact mechanism of GR actions in CRPC is still work in progress. There are studies suggesting that GR expression can be upregulated following antiandrogen therapy and can contribute to resistance to hormone therapies. Therefore, attempts are being made to develop selective glucocorticoid receptor modulators that specifically antagonize GR activity in CRPC, and thereby provide clinical benefit by blocking the GR mechanism for tumor growth. However, more targeted approaches are needed to understand the role of the GR-mediated target gene expressions in the CRPC that could in near future lead to better therapeutic options for patients with CRPC. This review highlights current perspectives on the actions of glucocorticoids during tumor progression and metastasis of CRPC.

Prognostic Significance of Glucocorticoid Receptor Expression in Cancer: A Systematic Review and Meta-Analysis

“…This data indicates that GR antagonist therapy may be most effective early in the disease, however further understanding of the biological signalling in chemotherapy treated tumours is required. In prostate cancer, GR expression and activation occurs following exposure to androgen receptor blockade and it is suggested to be an important resistance mechanism driving castration resistant tumour progression [ 18 , 70 ]. GR antagonists overcome androgen therapy resistance in pre-clinical prostate models and are currently in clinical trials for this indication (NCT03437941; NCT02012296).…”

“…Other hormonal receptors have been validated as biomarkers in cancer and have led to the development of tailored treatment regimens, e.g., oestrogen receptor (ER) in breast cancer. Unlike other steroid hormone receptors, the GR is not considered an oncogene although, emerging data suggests significant cross talk with oestrogen and androgen receptor signalling in hormone driven cancers [ 17 , 18 ].…”

Caudatin Isolated from Cynanchum auriculatum Inhibits Breast Cancer Stem Cell Formation via a GR/YAP Signaling

“…However, serious side effects, including the promotion of tumor growth and cancer metastasis, were occurred with GC clinical therapeutics [55]. Due to their lipophilic nature, GCs bind to GR, a specific receptor protein encoded by the NR3C1 gene that is expressed in almost all human cells, and GC-GR complex translocates into nucleus and regulates transcription of target genes [56]. Clinical evidence showed that the activation of GR induces chemoresistance and a poor prognosis in breast cancer patients [57].…”

Interplay of Epidermal Growth Factor Receptor and Signal Transducer and Activator of Transcription 3 in Prostate Cancer: Beyond Androgen Receptor Transactivation

“…As described in previous studies, PCa cells activate complementary growth signaling (GR and EGFR) and AR alternative splicing to overcome the absence of AR signaling in an ADT condition [ 18 , 35 ]. The EGFR maintains cell survival by the following main cascades: The SRC proto-oncogene, non-receptor tyrosine kinase (Src)/mitogen-activated protein kinase (MAPK) cascade, and phosphatidylinositol 3-kinase (PI3K)/AKT signaling.…”

“…The ligand-binding domain of AR variants is truncated into some constitutively active variants that provide growth signals even in androgen-ablated conditions [ 17 ]. In addition, the glucocorticoid receptor (GR) was found to be overexpressed in CRPC cells, which helped CRPC cells bypass AR signaling [ 18 ]. Particularly noteworthy is the fact that de novo CRPC-NE (CRPC-NE derived from NE cells) only occurred in approximately 1% of PCa cases and about 20% of CRPC cases [ 8 , 19 ], in which CRPC-NE development was partially induced by PCa treatment.…”