The role of glucocorticoid receptor in prostate cancer progression: from bench to bedside

Abstract

Glucocorticoids are a common class of adjuvant drugs for the treatment of castration-resistant prostate cancer (CRPC) combined with antitumour or antiandrogen agents. Glucocorticoids are administered clinically because they ameliorate toxic side effects and have inhibitory effects on adrenal androgen production, acting as a pituitary suppressant. However, their effects on prostate cancer cells especially the castration resistance prostate cancer cells are poorly defined. Glucocorticoids exert effects depend to a great extent on glucocorticoid receptor. In addition to a number of glucocorticoid receptor isoforms determined, it is found that the actions of glucocorticoids through GRα are influenced by other isoforms, such as GRβ and GRγ. Recently, studies found GR confers resistance to androgen deprivation therapy, and various glucocorticoids exert distinct efficacy in CRPC. In this review, we summarized the mechanisms of glucocorticoids and its clinical appliances on the basis of present evidence.

Therapies Targeted to Androgen Receptor Signaling Axis in Prostate Cancer: Progress, Challenges, and Hope

“…We also demonstrated a role of MYB, an oncogenic transcription factor, in androgen deprivation-resistant growth of PCa cells [212]. In some reports, a role of estrogen and glucocorticoid signaling in castration resistance is also reported [213][214][215][216]. We anticipate that novel therapies based on these resistance mechanisms will also be developed not in very distant future.…”

Immunoexpression of glucocorticoid receptor alpha (GRα) isoform and apoptotic proteins (Bcl‐2 and Bax) in actinic cheilitis and lower lip squamous cell carcinoma

“…This protein, which belongs to the superfamily of ligand‐dependent transcription factors, is maintained in an inactive state in the cytoplasm by association with heat‐shock proteins (HSPs). By interacting with glucocorticoids that cross the cytoplasmic membrane, GR dissociates from HSPs and translocates to the nucleus, where it can regulate gene transcription in a positive or negative manner . Among the five GR isoforms identified, GRα is the main responsible for the transcriptional activity of this receptor …”

“…High expression of GRα has been associated with indicators of less aggressive biological behavior in malignant neoplasms, such as smaller tumor size, early clinical stages, and higher survival rates of patients . These results have been attributed to the participation of GRα in immunoinflammatory responses, as well as cell proliferation and apoptosis . The mechanisms whereby GR modulates programmed cell death are poorly understood.…”

“…By interacting with glucocorticoids that cross the cytoplasmic membrane, GR dissociates from HSPs and translocates to the nucleus, where it can regulate gene transcription in a positive or negative manner. 7,8 Among the five GR isoforms identified, GRα is the main responsible for the transcriptional activity of this receptor. 9 High expression of GRα has been associated with indicators of less aggressive biological behavior in malignant neoplasms, such as smaller tumor size, early clinical stages, and higher survival rates of patients.…”

“…5,10,11 These results have been attributed to the participation of GRα in immunoinflammatory responses, as well as cell proliferation and apoptosis. 8,12,13 The mechanisms whereby GR modulates programmed cell death are poorly understood. It has been shown that overexpression of GR triggers the death of tumor cells, 14,15 possibly by inhibiting the expression of the antiapoptotic proteins Bcl-2 and Bcl-xL.…”